CN1486180A

CN1486180A - Methods for treating neuropsychiatric disorders with NMDA receptor antagonists

Info

Publication number: CN1486180A
Application number: CNA018217958A
Authority: CN
Inventors: 斯图尔特・M・D・利普顿; 斯图尔特·M·D·利普顿
Original assignee: NEWROMORICIUQU CO Ltd
Current assignee: NEWROMORICIUQU CO Ltd; Adamas Pharmaceuticals Inc
Priority date: 2000-12-07
Filing date: 2001-12-07
Publication date: 2004-03-31
Also published as: EP1351670A1; WO2002045710A9; MXPA03005130A; CA2436311A1; JP2004515477A; AU2002229056A1; EP1351670A4; WO2002045710A1; BR0116001A

Abstract

The present invention relates to compositions and methods for treating a human patient afflicted with a neuropsychiatric disorder. Specifically, the invention provides for compositions and methods of modulating or antagonizing the activity of neuronal NMDA receptors, wherein such antagonistic activity is capable of modulating the glutamate induced excitatory response of the neurons, thereby inhibiting an excitotoxic effect, promoting a neurotrophic effect, and thereby providing a therapeutic effect that treats the neuropsychiatric disorder.

Description

Method with nmda receptor antagonist treatment neuropsychiatric disorders

The present invention relates to treat the people patient's who suffers from the disease that comprises neuropsychiatric disorders compositions and method.Particularly, the invention provides and regulate or opposing neuron parent ionotropic glutamate receptor, compositions and method as nmda receptor, wherein so sharp anti-agent activity can be regulated neuronic activation and be replied, suppress to excite poisonous effect, promote close neural effect, thereby the treatment effect of treatment neuropsychiatric disorders is provided.

Background of invention

Nerve excitation aminoacid to these receptors, glutamic acid, particularly the receptor of N-methyl-D-aspartate (NMDA) hypotype is in neuronic growth, risen in function and the death pivotal role (referring to, Mc Donald J W et al., brain Review Study, 15:41-70 (1990) and Choi W, neuron, 1:623-34 (1998) is incorporated herein by reference).N-methyl-D-aspartate (NMDA) receptor is to exciting aminoacid glutamic acid, and glycine and synthetic compound N the MDA back joint conference and the ionotropic receptor of replying, so be called receptor.Nmda receptor combines bivalence (Ca with passage by receptor ²⁺) and unit price (Na ⁺And K ⁺) flow to postsynaptic neurocyte (referring to, Foster et al., natural 329:395-396 (1987); Mayer et al., pharmaceutical science trend, 11:254-260 (1990), the document is by being incorporated in this paper in this citation).

In growth course, nmda receptor has become entangled in the connection of neuronic structure and synapse, may participate in relying in the modification of synapse.In addition, nmda receptor is also thought and has been participated in secular potential energy, the plasticity of cental system (CNS), and inborn process, catching of memory is detained and study.In addition, nmda receptor has also caused special interest, because it has seemingly participated in broad-spectrum CNS disorder.For example, in shock or the cerebral anemia process that causes of wound, discharged the excessive aminoacid glutamic acid that excites from neuron damage or oxygen lack.This excessive glutamic acid combines nmda receptor, has opened the ion channel of part door, thereby allows Ca ²⁺Ca in the high-caliber cell is given birth in miscarriage ²⁺, activated the biochemistry cascade, cause protein, DNA, and membrane degradation cause cell death.This phenomenon is known to be to excite toxicity, also think relevant with nerve injury, with other disorders, relevant to insane crazy cardiac shock from hypoglycemia.In addition, have initial report to show, be included in Huntington equally, the chronic neural annealing of Parkinson and Alzheimer disease has participation.The activation of nmda receptor has shown to be had a responsibility for back shock convulsions, and in some models of epilepsy, the activation of nmda receptor has shown that to producing tic be essential.Animal Anesthesia PCP (phencyclidine) is to nmda receptor Ca ²⁺The checking of passage produced the plan mental status similar to schizophrenia (referring to Johnson et al., Annu.Rev.Pharmacol.Toxicol., 30:707-750 (1990), the document is by being incorporated in this paper in this citation) in the people.In addition, nmda receptor has also become entangled in the space learning of some types (referring to, Bliss et al., Nature, 361-31 (1993), the document is by being incorporated in this paper in this citation).What is interesting is upsetting of the room and time of the nmda receptor in mammalian nervous system has been found that it is vicissitudinous.So cell can produce nmda receptor at different time in their life cycle, and not all neurocyte can utilize nmda receptor.

Because its related neurological broad spectrum activity, and distribution heterogeneous, researcher has been placed on interest the evaluation and the exploitation of the medicine that can act on nmda receptor.Can regulate the medicine of nmda receptor and can expect to have huge treatment potentiality.For example, narrated for the 4th, 904, No. 681 by the United States Patent (USP) of authorizing people such as Cordi that is incorporated in this paper in this citation, the purposes of D-cycloserine, the known nmda receptor of can regulating provides and strengthens memory, the congenital defect that treatment is connected with neurological disorders.It is said that the D-cycloserine is a glycine antagonists, combines the insensitive Glycine Receptors of strychnine.

By be incorporated in the United States Patent (USP) the 5th of authorizing people such as Cordi of this paper in this citation, 061, No. 721, narrated in conjunction with utilizing the D cycloserine, with D alanine treatment Alzheimer disease, the memory impairment that age is relevant, study defective, disorderly and memory or the study of raising in healthy individual of psychosis.The D alanine in conjunction with the administration of D cycloserine, has been reduced the side effect in the clinical experiment of D cycloserine, and this mainly is because it to the growth inhibitory effect of antibacterial, causes peeling off of natural intestinal flower.The D-alanine has reversed the growth inhibitory effect of D cycloserine to antibacterial.Report has simultaneously, and the D cycloserine has part antagonism feature really.

By be incorporated in the United States Patent (USP) the 5th of authorizing people such as Trullas of this paper in this citation, 086, No. 072, narrated the purposes of 1-1-aminocyclopropane-1-carboxylic acid (ACPC), known is to regulate nmda receptor as the partial antagonist of the insensitive glycine binding site point of Semen Strychni, and the disorder that treatment is gentle comprises mainly containing depression, bipolar disorder, dysthymia and seasonal effective disorder.Wherein also narrated, ACPC has simulated the effect of the clinical effective antidepressant in the animal model.In addition, quote U.S. Patent application in a review as proof, wherein narrated ACPC and its derivant can be used for the treatment of the neurologic agent disorder that the excessive activation of nmda receptor causes.But, still exist needs to regulate the method for the satisfaction of nmda receptor function in this area.

Though need, the exploitation that target hits the medicine of nmda receptor is hindered, because the structure of nmda receptor is not also illustrated fully.Be sure of that it has comprised the several protein chains (subunit) that are embedded in the postsynaptic film.Two subunits of the beginning of Que Dinging have formed big zone, extracellular so far, may contain most other structure binding site, several ring formation stride diaphragm area, be folded to form permeable Ca ²⁺Hole or passage and have the still carboxyl terminal district of unknown function.The opening and closing of passage are regulated with combining of the zone that remains in extracellular proteins on surfaces by various parts, and separate from passage.Like this, these parts are all known is allosteric ligand.The combination (glycine and glutamic acid) of two common antagonist ligands is thought can influence the variation of the configuration in the proteinic total, and is finally to be reflected in opening of passage, partially opens, and part is closed or closed.Other allosteric ligands glutamic acid and glycine cause or the variation of the configuration that influences in conjunction with regulating.Believe that passage is a steady motion, changed cation by (opening) and cation blocked (closing) state.Unknown at present is that whether allosteric modulator has increased passage really is opened to the time of ion flow, or denys that instrumentality has increased the frequency of opening.Two effects can take place at one time.

Known several chemical compound, they are the antagonists by the anionic current of nmda receptor, but do not suppress the combination to the allosteric ligand in any known site competitively.These chemical compounds are combined in the inside of the cationic channel of opening, and known to the passage repressor usually.In fact, the repressor of such passage, (that is, the combination that contains tritium form MK-801) is a measure of good activation nmda receptor complex to dizocilpine.When passage was opened, MK-801 can freely pass through passage, in conjunction with the recognition site in the passage.On the contrary, when pathway closure, MK-801 cannot freely pass through passage and combination.When channel part was closed, opening fully than passage can be in conjunction with MK-801 still less.

Known passage repressor such as MK-801 and antagonist can protect cell can not excite toxicity death, but in their situation, healing may can not be achieved one's goal as dead, because any Ca that they check ²⁺Stream, thus any chance of recovering normal activity eliminated.Known passage repressor and glutamic acid site antagonist can cause hallucinations, hypertension, the loss of coordination, the formation of the cavity in the brain, the losing of the forfeiture of learning capacity and memory.PCP, typical passage repressor has produced the schizoid state of evident characteristic in the people.

Other bivalent cations such as Mg ²⁺And Zn ²⁺Can regulate nmda receptor.The accurate location of bivalent cation binding site remains unclear.Zn ²⁺Seemingly to the antagonism of having opened of passage, seemingly in conjunction with extracellular zone.Mg ²⁺Bifurcation activating curve when having shown a low concentration, this is the agonist of nmda receptor function, high concentration is the antagonist of receptor.As if seeming suitable function of receptors is absolute demand, combine a Mg in the passage ²⁺The binding site that relies on of voltage and the non-voltage in another zone, extracellular rely on binding site.These chemical compounds can be regulated nmda receptor, but are not to be suitable for long periods of treatment.Needs of this area are the chemical compounds safely and effectively of treatment neuropsychiatric disorders.

Gentle at present disorder may destroy secular effect, these sufferers and human illness, and the relation of production and the value of health care are huge.Recognize now, for many patients, be with incomplete recovery, secular result is often more dissatisfied than what think in the past, observes rapid decline (Goldbergand Harrow, 1996 in whole functional; Tohen et al., 2000).Really, according to the disease research of Global Burden, the disorder of emotion is in causing the main cause of worldwide undesirable condition, has seemingly represented bigger health in the future, the increase (Murray and Lopez, 1997) of society and economic problems.Many antidepressant are treated acute depression at present and can be got.Up to date decades, tricyclic antidepressants (TCA) is the depressed unique medicine that gets of treatment.Oxidase inhibitor (MAOI) can get, and utilizes now.Then, many novel drugs of quick successful novel drugs occurred, therein, that extensively utilize recently is 5-hydroxy tryptamine reuptake inhibithors (SSRI).Though select the Drug therapy depression to be the index ascendant trend in the past few decades, a set of equipment of present antidepressant continues to have the restriction of effectiveness and toleration.So, significant need exploitation new with improved most of depressed treatment.

Summary of the invention

The invention provides the method for treatment neuropsychiatric disorders, comprise nmda receptor antagonist chemical compound to patient's effective dosage of suffering from neuropsychiatric disorders, wherein this chemical compound can be regulated glutamic acid energy neurotransmission by receptor, thereby treatment or alleviation neuropsychiatric disorders, thereby provide the treatment effect.In one aspect, chemical compound provides powerful close neural effect by instructing intracellular mechanism.On the other hand, regulate a large amount of glutamic acid and can transmit, thereby mediate glutamic acid, thereby pass through neuroprotective effect the neuronic poisonous effect that excites.On the other hand, the nmda receptor antagonist chemical compound is regulated glutamic acid and can be activated cortex striped or end thalamus pallette approach.

In one embodiment, neuropsychiatric disorders is main depressed disorder.In another embodiment, neuropsychiatric disorders is bipolar disorder.Still in another embodiment, neuropsychiatric disorders is acute.Still in another embodiment, neuropsychiatric disorders is the relevant disorder of medicine, as the adding of medicine, and the dependence of medicine, the shrinking back of medicine, or the toleration of medicine.

The invention provides and utilize nmda receptor antagonist treatment to suffer from the depression of being mainly and, and provide the method for improving whole depressive symptom the chemical compound of patient's drug treatment effective dose not according to the psychotic patient of DSM-IV principle.In one embodiment, chemical compound is a Memantine hydrochloride.In another embodiment, chemical compound is a nitro Memantine hydrochloride derivant.

It is with relevant to replying of the treatment effect of chemical compound that the present invention also provides close neural effect that has a nmda receptor antagonist chemical compound among the patient of neuropsychiatric disorders in treatment and the change that determines whether the inductive glutamic acid of chemical compound (Glu) level in brain.In one embodiment, the present invention seemingly provides in the one pole depression assessment Memantine hydrochloride or the nitro Memantine hydrochloride derivant method to the influence of glucose metabolism.

The invention provides the purposes of the nmda receptor antagonist chemical compound that is mixed with the medicament that is used for the treatment of the patient who suffers from neuropsychiatric disorders.Nmda receptor antagonist chemical compound is chemical compound or its drug acceptable salt of general formula below the tool:

The radicals R of general formula ₁, R ₂, R ₃, R ₄And R ₅Be independent the definition.R ₁Be H, alkyl, assorted alkyl, aryl, heteroaryl, C (O) OR ₆Or C (O) R ₆R ₂Be H, alkyl, assorted alkyl, aryl, heteroaryl, C (O) OR ₆Or C (O) R ₆R ₃Be H, alkyl, assorted alkyl, aryl or heteroaryl.R ₄Be H, alkyl, assorted alkyl, aryl, or heteroaryl.R ₅Be OR ₇, alkyl-OR ₇Or assorted alkyl-OR ₇R ₆Be alkyl, assorted alkyl, aryl or heteroaryl.R ₇Be NO ₂, C (O) R ₆, C (O) alkyl-ONO ₂Or the assorted alkyl-ONO of C (O) ₂Following substituent group is preferred: R ₁And R ₂Be H; R ₃And R ₄Be H or alkyl; R ₇Be NO ₂Or C (O) alkyl-ONO ₂

The present invention also provides the pharmaceutical composition that can be used for the treatment of neurological disorders.Compositions comprises one or several chemical compound or its drug acceptable salt of drug acceptable carrier and following general formula:

The substituent group of chemical compound is independent definition.R ₁Be H, alkyl, assorted alkyl, aryl, heteroaryl, C (O) OR ₆Or C (O) R ₆R ₂Be H, alkyl, assorted alkyl, aryl, heteroaryl, C (O) OR ₆Or C (O) R ₆R ₃Be H, alkyl, assorted alkyl, aryl or heteroaryl.R ₄Be H, alkyl, assorted alkyl, aryl, or heteroaryl.R ₅Be OR ₇, alkyl-OR ₇Or assorted alkyl-OR ₇R ₆Be alkyl, assorted alkyl, aryl or heteroaryl.R ₇Be NO ₂, C (O) R ₆, C (O) alkyl-ONO ₂Or the assorted alkyl-ONO of C (O) ₂Following substituent group is preferred: R ₁And R ₂Be H; R ₃And R ₄Be H or alkyl; R ₇Be NO ₂Or C (O) alkyl-ONO ₂

The present invention also provides the method for treatment neurological disorders.This method comprises one or several chemical compound that can accept carrier and following general formula to patient's administration medicine, or its drug acceptable salt:

The present invention further provides to make and comprised the nmda receptor antagonist chemical compound of following general formula or the method for its drug acceptable salt:

Preferably, this method comprises the chemical compound of the general formula below the oxidation:

Preferably, the further nitrated chemical compound that comprises following general formula of this method:

Preferably, this chemical compound is treated in oxidation step with sulphuric acid and water.Denitrification step preferably includes with nitric acid and Ac2O and treats.

Brief description of drawings

Fig. 1 has shown the synthetic of adamantane nitric acid derivant.

Fig. 2 has shown the synthetic of adamantane ester derivant.

Fig. 3 has shown the synthetic of adamantane ester derivant that halogen and nitric acid replace.

Fig. 4 shows alkyl-ONO of adamantan ₂Synthetic.

Fig. 5 has shown the inhibition of the inductive apoptosis of NMDA in 7 pairs of cerebral cortex neurons of chemical compound.The cerebral cortex culture is contacted with 300uM NMDA, 20 millimeters with or do not contact with the chemical compound 7 of various concentration.By the dead culture of analyzing next day of neuronal cell program as described in example 19 above.The death of neuronal cell program is that chemical compound 7 can prevent (P＜0.001, n=3 cultivate) in all cases in dose-dependent mode.

Fig. 6 has shown after shock, in the mouse brain ischemia model, has reduced brain injury (referring to embodiment 20) relatively for drug compound 7 with contrast and Memantine hydrochloride.Utilize the intracavity sewing method to prove, (each organizes n=3), chemical compound 7 is effective (for contrast P＜0.03, for menamtineP＜0.05) reducing after the shock in the brain injury.

Fig. 7 shows, has relaxed pre-shrunk arteries (referring to embodiment 21) in the mode of dependent dose for drug compound 8.Fig. 7 a shows, 10 ^-6M has seen absent-mindedness, has seen absent-mindedness completely at 10.6M.Fig. 7 b has shown the effect of dosage.Fig. 7 c has shown by serge blue and has slowed down absent-mindedness.Fig. 7 d demonstration has slowed down absent-mindedness by hyperglobulinemia.

Fig. 8 shows that the effect of aminoadamantan derivant is special.Chemical compound 9 (a) and 10 (c) do not tell on, or slight vasoconstriction, the comparison that this can produce separately with solvent (EtOH).Chemical compound 7 (b) has produced the gentleest absent-mindedness in 10uM concentration.

Fig. 9 has illustrated the research with menantine, has shown its activation or antidepressant characteristic.

Detailed explanation of the present invention

The invention provides by suffering from the trouble of one or several neuropsychiatric disorders Composition and the side of NMDA hypotype glutamate receptor treatment neuropsychiatric disorders among the person Method. Be used for the neurotransmission that compound of the present invention has been regulated Glutamatergic, by carefully Mechanism in the born of the same parents provides or has brought into play huge close neural effect, thus treatment or alleviation The disorder of neuropsychopathy.

As used herein, " neuropsychiatric disorders " refers to acute and subacute disorder, do not have Neural and psychotic feature are arranged. Usually the example of neuropsychiatric disorders is to lead to Cross that the present invention treats, she comprises main depressed disorderly (MDD), and bipolar disorder is (hot-tempered Mad depression or BPD), anxiety, and pharmacological dependence are shunk back, and drug tolerance, The disorder that damage produces, ischemic or anoxic symptom comprise shock, chorda dorsalis injury, head decreases Hinder, enclose living phase hypoxemia, the neural damage of heart shock and hypoglycemia, epilepsy, Alzheimer Disease, the Hunt6ington disease, Parkinson's disease, the amyotrophia after-hardening is fainted from fear, pain, Schizophrenia, muscle cramp, antimigraine, the urinary incontinence, vomiting, encephaledema, late The dyskinesia of sending out, the dementia that AIDS induces, the eye damage, the retina disease, cognitive disorderly Disorderly, infect relevant nerve damage as cognitive motion and sensory function imbalance with HIV. Neuropsychiatric disorders has narration, the 4th in the diagnosis of abalienation and statistics handbook Version, U.S. psychiatry publishing house (1994), the document is by being incorporated in this citation This paper.

As used herein, " nmda receptor antagonist compound " refers to aminoadamantan Derivative such as U.S. amantadine, the firm amines of nitro U.S. dollar, with relevant U.S. amantadine and The firm amine derivative of nitro U.S. dollar wherein utilizes U.S. amantadine to hinder as the NMDAR passage Hold back the redox modulating site on thing and the nitrogen oxide kind adjusting nmda receptor. This The nmda receptor antagonist compound of sample specifically sees United States Patent (USP) the 6th, 071,876, 5,801,203,5,747,545,5,614,560,5,506,231 and PCT application 01/62706 In number, all be to authorize Lipton, the people's such as S.A., these documents by in this citation and Be incorporated in this paper.

As used herein, term " alkyl " refer to up to the not replacement of 15 carbon atoms or The linearity that replaces, branch, or cycloalkyl carbochain. The linear alkyl group for example comprises, Methyl, ethyl, N propyl group, N butyl, N amyl group, N hexyl, N hexyl, N certain herbaceous plants with big flowers Base. The alkyl group of branch for example comprises, isopropyl, sec butyl, isobutyl group, uncle Butyl and neopentyl. Group of naphthene base for example comprises, cyclopropyl, cyclobutyl, ring penta Base and cyclohexyl. The alkyl group can replace with one or several substituting group. Like this The non-limitative example of substituting group comprises NO₂，ONO ₂，F，Cl，Br，I，OH，OCR ₃， CO ₂H，CO ₂CH ₃, CN, aryl and assorted aryl. When utilizing in the text " alkyl " Such as " alkyl-ONO₂" time, it refers to use ONO₂The alkyl group that composition replaces. When Utilize in the text " alkyl " group such as " C (O) alkyl-ONO₂" time, it refers to that the alkyl group is connected a position with the carboxyl group, and uses ONO₂Composition replaces.

As used herein, term " assorted alkyl " refers to that the carbon atom in the chain contains one at least Individual hetero atom (as, nitrogen, oxygen or sulphur) do not replace, or the linearity that replaces, branch or Loop chain. Linear assorted alkyl group for example comprises CH2CH2OCH3, CH₂CH ₂N(CH ₃) ₂And CH₂CH ₂SCH ₃ Branch's group for example comprises, CH₂CH(OCH ₃)CH ₃， CH ₂CH(N(CH ₃) ₂CH ₃And CH₂CH(OCH ₃)CH ₃ The assorted alkyl group of ring comprises For example, CH (CH₂CH ₂) ₂O，H(CH ₂CH ₂)NCH ₃And CH (CH₂CH ₂) S. Assorted The alkyl group can replace with one or several substituting group. The non-limit of such substituting group Example processed comprises NO₂，ONO ₂，F，Cl，Br，I，OH，OCR ₃，CO ₂H，CO ₂CH ₃, CN, aryl and assorted aryl. " assorted alkyl " that utilizes in its Chinese as " assorted alkyl-ONO₂" refer to use ONO₂The assorted alkyl that composition replaces. " the assorted alkyl " that utilizes in the literary composition Such as " C (O) alkyl-NO that mixes₂" refer to be connected the alkyl group, and use ONO a position with carbonyl₂Composition replaces.

As used herein, term " halogen " refers to F, Cl, Br or I.

As used herein, term " aryl " refers to not replace, or the carbon of the fragrance that replaces Cyclic group. Aryl is single or a plurality of concentrated cycle compounds. Phenyl group for example Single ring, aromatic yl group. There is the example of the aromatic yl group of a plurality of concentrated rings that naphthalene is arranged Group. Aromatic yl group can replace with one or more substituting groups. Such substituting group Unrestricted example comprise NO₂，ONO ₂，F，Cl，Br，I，OH，OCR ₃，CO ₂H， CO ₂CH ₃, CN, aryl and assorted aryl.

As used herein, term " assorted aryl " refers to have at least one in aromatic rings The assorted aromatic group that does not replace or replace that closes atom (for example, nitrogen, oxygen or sulphur). Assorted virtue The base group is single ring or a plurality of concentrated cycle compound. At least have the single of a nitrogen The ring heteroaryl group for example comprises, tetrazole radical, and pyrrole radicals, pyridine radicals, the pyridazine base, Indyl, quinoline base, imidazole radicals, isoquinolin base, pyrazoles base, pyrazine base, pyrimidine Base, pyridazinonyl. Furyl for example is the heteroaryl groups of monocycle, contains one Oxygen atom. The example that contains the ring heteroaryl group that concentrates of an oxygen atom is the benzene furan The group of muttering. Thienyl group for example is the bicyclic heteroaryl group, contains a sulphur atom. The example that contains the ring heteroaryl group that concentrates of a sulphur atom has the benzene thiophene aryl of mixing Group contains more than one the assorted atom that closes in same ring. The example of such group Attached bag is drawn together the furazan base, oxazolyl, different oxazolyl, thiazolyl and phenol thiazolyl. Assorted virtue The base group can replace with one or several substituting group. Such substituting group unrestricted Example comprises NO₂，ONO ₂，F，Cl，Br，I，OH，OCH ₂，CO ₂H，CO ₂CH ₃, CN, aryl and assorted aryl.

As used herein, " treatment effectively " refers to such as technology for detection disclosed herein, and be basic The clinical observation signal and the symptom of neuropsychiatric disorders observable improvement is arranged.

Term " medicine can be accepted " refers to lack in compound such as salt or excipient can not The toxicity of accepting. Drug acceptable salt comprises inorganic anion, such as chlorine, and bromine, allusion quotation, Sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid etc. Organic anion such as acetic acid, Malonate, malic acid, propionic acid, cinnamic acid, toluene fulfonate, citric acid etc. Medicine can be accepted excipient such as E.W.Martin described in the Remington medicine science (Mack Pub.Co.).

As used herein, " instructing intracellular mechanism " refers to promoting neuroprotective and stoping thin The effect of signalling approach and damage approach in the cell of born of the same parents' death (programmed cell death).

As used herein, " Glutamatergic neurotransmission " refers to, the nerve cell in brain Between the cynapse transmission, thereby the presynaptic cell from the postsynaptic cell discharges paddy ammonia Acid is in conjunction with glutamate receptor, thus the electric current in the initiation postsynaptic cell. This process Between nerve cell, produced the information transmission. In situation as referred to herein, Tangle the glutamate receptor on the cynapse cell in the pathogenic physiology of neuropsychopathy symptom The type of body is the NMDA hypotype of glutamate receptor.

As used herein, it is short of money anti-that " close neural effect is provided " refers to reply nmda receptor The rise of signalling approach strengthens neuronic survival in the cell of thing, and usually It is the adjusting that is subjected to the close neural factor (BDNF) of close neural factor such as brain origin.

As used herein, " reducing depressed disorderly pathogenic property " refers to fall in the event below Low, comprise the particularly depression of the overstimulation of nmda receptor hypotype of glutamate receptor.

As used herein, " the excessively event of glutamate induction " refers to the overstimulation of glutamate receptor, causes excessive Ca²⁺Stream, the formation of free free radical is with relevant refreshing Through cell toxicity, damage, even the other biological chemical event of cell death is (because bad Dead or programmed cell is dead).

As used herein, " substantially not having dopamine or noradrenaline element " refers to deficiency With cause and enlarge in the cynapse cell activity can the concentration of these neurotransmitters.

The neuropsychopathy emotionally disturbed is such as adult's depressed disorderly (MDD) and bipolar disorder (manic-depressed sick, be common BPD), serious, chronic and frequent life Compromised disease. Commit suiside to estimate be up to the individuality of suffering from MDD 15% dead The reason of dying, except committing suiside, the relevant impact of many other disadvantageous health More and more clearly recognize (referring to, Musselman et al., 1998; Schulz et al., 2000, the document is by being incorporated in this paper in this citation). With pure mental symptoms Disease different be, MDD is the disease of system, it is unfavorable that a plurality of organ system is had Impact. For example, MDD is the myocardium infarct of blood vessel advancing of disease and index The main hazard factor of rear death. In addition, nearest about the physics disease, smoke Find with the research that ethanol consumes, press down to the not enough similar height of shock and congenital mental and physical efforts The death risk order of magnitude that the existence of strongly fragrant symptom provides improves. Sending out again of the paroxysm that produces The accumulation effect of doing causes breaking of marriage and family, unemployment, and affected occupation is sent out The speed of exhibition and financial difficulties subsequently increases. With dead relevant with ability decline and morning Consume singly the U.S. have every year 10 hundred million dollars financial burden (Greenberg et al., 1990; Wyatt and Henter, 1005, the document is by being incorporated in this in this citation Literary composition). So what be not taken aback is that the burden of global disease research is identified, MDD The main cause of worldwide ability decline, with as if representative increases gradually in future The health that adds, the disease of society and the ÷ of economic problems similar (Murray and Lopez, 1997, the document is by being incorporated in this paper in this citation). Suicide be suffer from bipolar and Reproduce the 10-20% Factors of death in the disorderly individuality of depression. Although MDD pair Worldwide 1,000,000 life has destructive impact, about they the cause of disease or cause The cause of disease reason is known seldom. In addition, although can obtain widely antidepressant medicine, Clinical trial shows that 30% to 40% depressed patient can not be replied first-line anti-pressing down Strongly fragrant treatment, although dosage, tolerance all is suitable (Nierenberg, 1994 with answering sex change; Thase and Rush, 1995, the document is by being incorporated in this paper in this citation).

It is verified that form is measured neural imaging research, patient's tool of BPD and MDD The variation of tangible attitude amount, show as cell loss and/or organ atrophy (Drevets et al., 1997; Drevets, 1999; Sheline et al., 1996; 1999, the document is passed through at this Citation and be incorporated in this paper). The neural imaging of capacity studies show that to suffer from emotionally disturbed The patient in, the 3rd and the ventricle of rear side enlarge, and at socket of the eye and inboard forehead skin Layer (PFC), the grey matter volume reduces (Drevets, 1999 in abdomen corpus straitum and the nearly middle temporo cortex; Sheline et al., 1996; 1999). And family one pole depressed at BPD presses down recently In strongly fragrant verified and the abdomen of the knee of end body in average grey matter volume in the zone of locating Have an appointment 40% minimizing, the frontal lobe volume also reduces (Drevets et al., 1997). Having Also observed the minimizing of hippocampus volume in the main body of MDD history, this can press down Strongly fragrant paroxysm solved and continued 10 years afterwards (Bremner, et al., 2000, the document by This citation and be incorporated in this paper; Sheline et al., 1996; Sheline et al., 1999). Lose the hippocampus volume and as if be lasting relevant with total life time of MDD (Sheline et al., 1999) have produced these and have changed repetition and/or the prolongation that represents depression Formulation (Brown et al., 1999 of sequelae of paroxysm; Sapolsky, 2000).

Now, many researchs show, abnormal low brain N-acetyl asparagus fern ammonia Acid (NAA) is measured and can be increased, even the amyotrophia after-hardening is arranged such as the demyelinate disease (ALS), mitochondria encephalopathic, the CNS symptom in the disorder of the dementia relevant with HIV The normalization (Tsai and Coyle, 1995) of alleviation. NAA is commonly referred to be god now Through the measurement index of first existence power and function, rather than as the mark of neuron loss (Tsai and Coyle, 1995). In the nearest high-resolution nuclear magnetic resonance spectroscopy imaging that utilizes In the research of method, Bretolino et al (1999) finds, and compares BPD master The NAA level of the two sides in the hippocampus of body descends. With comparing of health, at BPD Also find NAA's in two sides in the back of the body outside prefrontal cortex (DLPFC) among the patient The decline of level (Winsberg et al., 2000). These researchs and neurochemistry are supported feelings Thread is disorderly relevant with the minimizing of regional neuron loss and/or neuronal survival power/function, Physics and physiological orientation to disorder have been explained. Except accumulating neural imaging evidence, several The research of individual brain after death provides regional CNS volume, cell number and cell now The minimizing of body size. Baumann and partner (1999) report is from one pole MDD Or right side nuclear is examined according to the shape body in the left side in the after death brain sample that obtains among the patient of BPD Shell and the outer volume of two side ash spheroids reduce. Several nearest PFC are three-dimensional research after death Also verified, regional volume, cell number and/or size reduce. With control patients Relatively, the shape of the density of the unit of the cortex neural in DLPEC and socket of the eye volume cortex and size The attitude quantitative analysis has been found that obvious minimizing in the patient of emotionally disturbed (Rajkowska et al., 1999; 2000). On the whole, from neural imaging research Data and the advantage of the evidence of health after death growth represented a believable situation That in suffering from patient's subbreed row of emotionally disturbed, regional CNS volume is certain at least Reduce, followed atrophy and losing of cell (neuron and colloid) in some cases.

The impact of anti depressant therapy on the cells survival approach

The factor that participates in neuron atrophy and the existence is anti depressant therapy of the present invention Target. At cells survival and the relevant weight that participates in the plasticity of close neural effect that provides Want approach for example to comprise, cAMP-CREB cascade, and CREB target, brain rises The close neural factor (BDNF) in source. These can raise by anti depressant therapy (Duman et al., 2000, be incorporated herein by reference). CREB and BDNF's is upper Readjust the distribution to be born in and reply in several different anti depressant therapy classifications, comprise NE, and SSRI Twitch with electrofit, show that cAMP-CREB cascade and BDNF are the treatment compounds Common acceptor after target (Nibuya et al., 1995,1996). In addition, CREB and The rise of BDNF depends on chronic treatment, is and antidepressant treatment action one Cause. Depressed behavior mould has been strengthened in the rise of CAMP-CREB cascade and BDNF The performance of type (Duman et al., 2000). Anti depressant therapy has produced similar neurophilic Effect is such as the bigger regeneration of splitting cholamine crystal terminal in cerebral cortex (Nakamura, 1990). It is excessive to utilize nmda receptor antagonist compound to regulate The activity of glutamatergic system provides close neural effect to patient, thereby has reduced this The pathogenic factor of one neuropsychiatric disorders.

NMDA antagonist and the antidepressant activity that influences the glutamic acid neurotransmission

Depressed monoamine hypothesis is that the effect of drugs for early stage drug development grows up, and it no longer provides the explanation of the satisfaction of the mode of behavior in the paathogenic factor in all antidepressant compounds or the following depression.In generation nineteen fifty, it is reported that at the partial agonist as the nmda receptor glycine site of the part of multiple medicines thing antituberculosis therapy, the D cycloserine has emotion and promotes effect (Heresco-Levy and Javitt, 1998).Then, the evidence of the associating between the pathology of change brain glutamic acid energy neurotransmission and emotionally disturbed increases.The health of pre-clinical research growth shows the pathology of the depression that the NMDA classification of glutamate receptor can participate in being grown up and antidepressant action mechanism (Skolnick et al., 1999).Nmda receptor antagonist such as MK-801 and AP-7 are verified at the animal model of depression, comprise and inevitably swash the application of answering thing, forced swimming, the tail inductive fixedly experiment that suspends, at the helpless model of the understanding of depression, in the animal of using chronic gentle compressing method, antidepressant effect (Hauang, 1997 are arranged; Paul, 1997).On the contrary, the administration of antidepressant shows, produces nmda receptor function (Nowak et al., 1993,1995) and receptors bind mode (Paul et al., 1994).In addition, the support of the fact below the effect of the glutamic acid energy functional disorder in depression is subjected in addition, promptly multiple antidepressant administered area ground has changed expression (Boyer et al., 1998 of the mRNA of a plurality of nmda receptor subunits of encoding; Skolnick, 1999) and combine (Skolnick, 1999) of radioligand and these receptors in central nervous system's (CNS) scope zone.In brief, behavior and neuro chemistry studies show that the NMDA antagonist has produced similar in appearance to the variation of the neuro chemistry of antidepressant medicine in brain, and they have shown the way of act of similar antidepressant in some depressed animal models.Pre-clinical evidence shows that the existing antidepressant of chronic administration has been brought into play tangible damping (albeit complex) effect to glutamatergic system.In addition, many compressing examples are be sure of by the neurotransmission that strengthens the glutamic acid energy hippocampal formation have been brought into play many disadvantageous effects.Say that on the whole the excessive activity of regulating glutamatergic system provides the method for the pathology of treatment neuropsychiatric disorders.More particularly, damping glutamic acid active compositions of energy and method provide suffering from the method that depressed disorderly patient treats antidepressant effect.

The nmda receptor antagonist

The potential effect of given glutamic acid in CNS damage and neurodegenerative disease, several therapeutic schemes have been used to reduce the toxicity that excites that glutamic acid mediates.An approach comprises and utilizes nmda receptor antagonist chemical compound.But he is because of obtaining research in depression, but with develop into psychotic dangerous increase relevant.In double blinding, the Lamotrigine in the research of placebo control it is reported in acute bipolar depression effectively (Calabrese et al., 1999).In the one pole depression, find lamotrigine to HAMD project 1 and CGI serious change the last observation carried out but in the HAMD of total score and MADRS than placebo superior (Laurenza et al., 1999).Though the accurate mechanism of the behavior of lamotrigine is also unknown, suppress excessive release glutamate and be to be assumed to (Calabrese et al., 1999) of similar mechanism of the action of this medicine.May preferably influence glutamic acid can the medicine of neurotransmission can be in some subgroups of the patient of depression effectively.The chemical compound that some subgroups (but the utmost point and bipolar depression) that accurately determine whether depressed patient are seemingly replied to diversity the antiglutamic acid energy needs other research.Such chemical compound reduces the release of glutamic acid and has been presented at Parkinson disease; dull-witted; ischemia; with in the animal model of the CNS damage of damage neuroprotective being arranged is nmda receptor antagonist menamtine; it does not resemble other glutamate receptor antagonists; prove as the patch relevant-pincers electrophysiological recording with behavioral study; the electric current that has seemingly separated normal neurotransmission and only stoped excessive glutamate induction is (referring to Chen et al., 1992,1988; Chen and Lipton; 1997, Lipton, 1993; Lipton and Rosenberg 1994, the document is by being incorporated in this paper in this citation).

Memantine hydrochloride (Akatinol Memantine , (Merz﹠amp; Co., GmbH) CASRegistry No.41100-52-1), be to be used for the treatment of dementia symptom at present, the tetanic and Parkinsonian noncompetitive N-methyl-D-aspartate of spinal cord (NMDA) antagonist.Chemically, Memantine hydrochloride is the 1-amino-3 of adamantane, the 5-dimethyladamantane.With other NMDA antagonists relatively, it is maximum in PCP and the bonded effective potentiality of MK-801 acceptor site (fKornhuber et al., 1991) to be reported that Memantine hydrochloride has in human brain tissue.In treatment concentration, the PCP and the MK-801 binding site (Kornhuber et al., 1989) of the nmda receptor in the Memantine hydrochloride combination volume cortex after death, and reduced membrane current (Bormann, 1989).Memantine hydrochloride has fine toleration, although and it be extensive use of in Germany, have only minority independently the case report of psychosis and cognitive defect its use is arranged.As if compare other NMDA antagonists, menamtine seemingly has more favourable pharmaceutical admixtures, and does not more induce psychosis and cognitive defect.Binding isotherm does not have negligible influence because of it to hypothalamic pituitary axis (HPA) as him owing to compare other NMDA antagonists but why Memantine hydrochloride does not seemingly induce cognitive defect and psychotic probability to be.Nmda receptor has been reported the adjusting of beating (Bhat et al., 1995) that has participated in from the hormone of hpa axis release, causes hydrocortisone too much.Psychotic symptoms in depression is connected (Walder et al., 2000) with secondary in the active wild phase of the too much active dopamine of HPA with cognitive defect.Lack Memantine hydrochloride to the influence of hpa axis and the psychotic low ratio of utilizing this medicine to see that caused the active enhancing possible explanation of dopamine.Memantine hydrochloride is opposite with dextromethorphan to another advantage of other NMDA antagonists, and Memantine hydrochloride does not have active metabolism, has NMDA antagonistic properties (Ziemann et al., 1996).In addition, the Memantine hydrochloride serum levels can be measured.Memantine hydrochloride is a few NMDA antagonist that gets that can utilize in the people, and be the depression that can be used for treating the adult as the precursor amantadine of itself and it ideally, used side effect very little (Kornhuber et al., 1994) clinically many years.Memantine hydrochloride seldom with as other MNDA antagonists such as phencyclidine and the significant side effects of Ke Ta because of seeing, excitement, chaotic relevant (Rabey et al., 1992 with psychosis; Riederer et al., 1991).Memantine hydrochloride is to be accepted by the old people, and therefore, in Europe, it is through being often used as prescription drugs (people such as Gortelmeyer, 1992).

Memantine hydrochloride has the neural and activation characteristic of tangible parent, and it can be used to regulate glutamic acid energy neurotransmission, and simultaneously by instructing intracellular mechanism that huge close neural effect is provided.Memantine hydrochloride has the NMDA antagonist characteristic that potential noncompetitive voltage relies on, effect can compare with MK-801 (referring to, Bormann, 1989, the document is by being incorporated in this paper in this citation).Memantine hydrochloride also proves convulsion and neuroprotective properties and external dopaminergic effect (referring to, Mai, 1982, the document is by being incorporated in this paper in this citation).Memantine hydrochloride was brought into use from 1978, in Germany is to agree that treatment has the disorder of brain performance of poisoning of gentleness of the brain symptom of project: concentrate and disturbance of memory, forfeiture interest and driving force, precocious fatigue, and dementia symptom, improve in the disease of attention and Vigilance at needs.Brain and spinal cord are tetanic, and parkinson and similar Parkinson disease are other indications.The effect of Memantine hydrochloride is the instrumentality as glutamic acid energy neurotransmission.In the state of the release of minimizing glutamic acid, Memantine hydrochloride has caused the raising of signal transmission and neuronal activation after deterioration of neurons.In the state that a large amount of glutamic acid discharges, as ischemia, Memantine hydrochloride has stoped mediation glutamic acid to the neuronic nmda receptor that excites toxic action.Be sure of that its neuroprotective properties is owing to nmda receptor antagonist in pathology increases glutamic acid.The effectiveness of Memantine hydrochloride in parkinson disease has shown the result of the enhanced active ability that is its neutralization (or adjusting) glutamic acid energy cortex stricture of vagina and thalamus cpopallidal approach.(Klockgether and Turski, 1989,1990, andSchmidt et al., 1990, the document is by being incorporated in this paper in this citation).This effect is to be independent of dopamine or norepinephrine release.

Memantine hydrochloride was in the news many years, all defect symptom or the depressive symptom of finding usually in other neuropsychiatric disorders such as Parkinson disease and dementia was usually had male effect.In the research of suffering from dull-witted and Parkinsonian patient, depressed emotion, anxiety lacks power, the body constitution disorder, the damage of vigilance, impermanent memory can obviously improve with Memantine hydrochloride with concentrating.In these researchs some are also reported and are utilized Memantine hydrochloride to have activity too much, unpeace, and euphoriant unfavorable effect shows that it may have the characteristic of activation or antidepressant.These discoveries are summarised in the table shown in Figure 9.

The pharmacology of Memantine hydrochloride

Memantine hydrochloride is to absorb fast and fully, and in fact is being and people's albumin uncombined (＜10%).Its disappearance is a bifurcation.When the mean half-life of Memantine hydrochloride report is the begin treatment correlation behavior 4-9 hour is 40-65 hour during second attitude then.The 75%-90% that disappears occurs in the kidney approach at first, and defecate only accounts for 10%-25% (Weseman et al., 1980).The side effect of Memantine hydrochloride is a dependent dose, comprises and dozing off, and internally with mobility's unpeace and excitement, fatigue, cephalemia and feeling sick.Some independently chaotic and psychotic situations have had report, but these patients also have the medical conditions of unanimity, and have also accepted L-dopa or amantadine (Rabey et al., 1992; Ditzler, 1991).The raising of locomotor activity and in high spirits or dizzy also the report occur in the treatment that utilizes Memantine hydrochloride.The drug reaction that utilizes Memantine hydrochloride is normally gentle, and has reported and occur in barbiturate, neuroleptics, cholinolytic element, L-dopa, dopaminergic element, agonist and amantadine.

Nmda receptor antagonist chemical compound of the present invention comprises the aminoadamantan derivant that can be mixed with the medicament of suffering from drug acceptable salt or be mixed with the pharmaceutical composition that further contains excipient.Memantine hydrochloride and nitro Memantine hydrochloride derivant be to people patient at the dosed administration of dosage range 0.1-1000mg/day, but Memantine hydrochloride is fine in the tolerance of dosage 100-500mg/day.The dosage of nitro Memantine hydrochloride chemical compound is the 1-100 mg/day normally, and similarly can tolerate.In the people, the serum levels of Memantine hydrochloride coverage is 0.25-0.529uM in 5 and 30 mg/day.In these similar patients, the CSF horizontal extent 0.122-0.053uM of Memantine hydrochloride, and with the blood serum values height correlation (r=0.99, p=0.0018).Average CSF/ serum ratio is 0.52 (referring to, Kornhuber and Quack, 1995, the document is by being incorporated in this paper in this citation).When these concentration (0.1 to 1000 mg/day), Memantine hydrochloride specifically with the PCP of nmda receptor or the reaction of MK-108 binding site (Kornhuber et al., 1994; Kornhu7ber and Quack, 1995), and be when receptor is regulated glutamic acid energy neurotransmission, be effective.

Nmda receptor antagonist chemical compound in administered in pharmaceutical compositions is blended with appropriate carriers, so that has had the treatment effective dose in the compositions.Term " treatment effective dose " refers to that the amount of chemical compound is the purpose needed (for example, reducing the result's of shock neuronal damage) that obtains needs.Like this, the therapeutic purposes in dosage are thought the result by the development of the therapeutic effect among the patient, and are determined as mensuration disclosed herein and technology.The medical professional can determine the suitable dosage of Memantine hydrochloride, regulates the dosage as the patient up or down who needs, and therapeutic effect is provided and reduces disadvantageous side effect.But will be appreciated that, any specific patient's specific dosage level will depend on various factors, the activity that comprises the specific compound of utilization, age body weight, general health status, sex, diet, time of administration, the approach of administration, excretory speed, the combination of medicine and the specific severity of disease for the treatment of.

Nmda receptor antagonist chemical compound, (reactive compound 0 can be oral for its enantiomer or drug acceptable salt, partly, hypodermically, administration by the intranasal that sucks or spray, or can accept carrier to contain conventional non-drug toxicity with rectum ground, the dosage unit prescription of adjuvant and carrier comes administration.Can give birth to the single dose form in conjunction with the volume production of the reactive compound of carrier mass, will depend on the host of treatment and the specific mode of administration.The subcutaneous subcutaneous injection that comprises of term as used herein, intravenous, intramuscular, intrasternal syringe or perfusion technique.In addition, the invention provides the pharmaceutical formulation that contains nmda receptor antagonist chemical compound and drug acceptable carrier.Reactive compound can be in conjunction with one or several atoxic drug acceptable carrier and/or diluent and/or adjuvant and is existed, and if desired can be in conjunction with other active component.The pharmaceutical composition that contains reactive compound can be the form that is suitable for orally using, tablet for example, lozenge, lozenge, aqueous solution or oil suspension, dispersible powder or granule, emulsion, hard or soft capsule or syrup or the agent of speeding.

Planning the compositions of oral utilization can prepare according to methods known in the art, be used to make pharmaceutical composition, such compositions contains one or several and is selected from and comprises edulcorant compound, the flavoring agent chemical compound, the chemical compound of toner chemical compound and preservative compounds is so that provide pharmacology to be particular about and good to eat preparation.Tablet contains reactive compound, has mixed the non-drug toxicity of the manufacturing that is applicable to tablet and can accept excipient.These excipient can for example be the toxicity diluent, as calcium carbonate, and sodium carbonate, lactose, calcium phosphate, and sodium phosphate; Granular and abstersive chemical compound, for example corn starch, or alginic acid; Binding compounds is starch for example, gelatin or arabic gum, and lubricant compound is magnesium stearate for example, stearic acid or Pulvis Talci.Tablet can be a coating not, or they can come coating by known technology, or postpones decomposition and absorption in intestines and stomach, thereby the effect that continues in longer period is provided.For example, can utilize material such as the glycerol monostearate or the glycerol disterate of delay.

The prescription of oral utilization also can be used as hard gelatine capsule and exists, wherein active component be with the toxicity solid diluent for example, calcium carbonate, calcium phosphate or Kaolin mix, or as soft gelatine capsule existence, wherein active component is and water or oily medium for example Oleum Arachidis hypogaeae semen, liquid paraffin or mixed with olive oil.

Aqueous suspension contains and is suitable for making the active substance of the mixed with excipients of aqueous suspension.Such excipient is a suspended mixture, sodium carboxymethyl cellulose for example, methylcellulose, hydroxypropyl emthylcellulose, sodium alginate, polyvinylpyrrolidone, Huang Shi glue, and arabic gum, dispersive or moistening chemical compound can be naturally occurring phosphoric acid fat, lecithin for example, or have the enriched product of the methylene oxide of fatty acid, stearic acid polyoxyethylene for example, or has an enriched product of the ethylene oxide of long-chain fatty alcohol, for example 17 caethyleneoxycetanol, or ethylene oxide and originate from part ester and the hexanol such as the single oleic enriched product of polyoxyethylene sorbitol of fatty acid, ethylene oxide and originate from the part ester of fatty acid and the enriched product of hexanol anhydride, for example polyethylene sorbose list oleic acid.Aqueous suspension also can contain one or several antiseptic, for example ethyl, or n-propyl group p-hydroxy benzoic acid, one or several toner chemical compound, one or several flavoring agent chemical compound and one or several edulcorant compound such as sucrose or glucide.

Oily suspensions can with active component at vegetable oil for example pass through, Oleum Arachidis hypogaeae semen, and olive oil, Oleum sesami, Oleum Cocois, or oily in mineral nitrogen as the suspended active ingredient in the liquid paraffin.Oil suspension can contain thickening compound, for example Cera Flava, hard paraffin or acetyl ethanol.Edulcorant compound such as those foregoing those, the flavoring agent chemical compound can add, and exquisite oil formulation is provided.These compositionss can add antioxidant such as ascorbic acid comes anticorrosion.

Provide active component but be suitable for adding dispersed powders and the granule that entry prepares water slurry, mixed dispersive or moistening chemical compound, suspended compound and one or several antiseptic.The example of suitable dispersion or humidification compound or suspended compound has those already mentioned above.Other excipient, sweeting agent for example, flavoring agent and toner chemical compound also exist.

Pharmaceutical composition of the present invention can also be the emulsion of oil-in-water form.Oil phase can be a vegetable oil, olive oil for example, and Oleum Arachidis hypogaeae semen, or mineral oil, as liquid paraffin, or their mixture.The examples of suitable emulsifiers chemical compound can be natural natural gum, for example, and Radix Acaciae senegalis, gum tragacanth, natural phospholipid is as Semen sojae atricolor, lecithin is by fatty acid and deutero-fat of hexitol or part fat, acid anhydride, as the sorbitan monoleate, the condensation substance of described part fat and oxirane, for example, sweeting agent, flavoring agent, hyperchromic chemical compound etc., they can be present in the compositions.

Syrup and speed agent can with edulcorant compound glycerol for example, propylene glycol, sorbitol or sucrose are prepared together.Such prescription also can contain demulcent, antiseptic and flavoring agent and toner chemical compound.Pharmaceutical composition can be the aqueous solution or the butyraceous suspension of sterile injectable.This suspension can utilize those suitable dispersions or moistening chemical compound and the suspended compound of having mentioned to prepare in the above according to known field.Aseptic injectable formulation also can be aseptic Injectable solution or the suspension in subcutaneous acceptable diluent of non-toxicity or the solution, for example as 1, and the solution of 3-butanediol.In utilizable acceptable carrier and solution is whom, Ringer solution, isoosmotic sodium chloride solution.In addition, aseptic, fixed oil is conventional the utilization as solution or suspension media.For this purpose, the oil of Mixed Stationary can utilize, and comprises synthetic single or two glycerol.In addition, fatty acid such as oleic acid have been found purposes in injectable preparation.

Reactive compound also can be with the suppository form administration of rectally medicine.These chemical compounds can prepare by hybrid medicine and suitable non-stimulation excipient, and excipient is the solid under the temperature generally, but at the liquid that rectal temperature is, so dissolve in the universal love owner-peasant rectum, discharge medicine.Such medicine is Oleum Cocois and Polyethylene Glycol.

Reactive compound can be at subcutaneous form administration with aseptic medium.Medicine according to carrier and concentration can be suspension or be dissolved in the carrier.Advantageously say, adjuvant such as local anesthetic, antiseptic and buffer compounds can be dissolved in the carrier.

Chemical compound of the present invention is the nmda receptor antagonist, comprises aminoadamantan derivant such as Memantine hydrochloride, nitro Memantine hydrochloride or the like.The nmda receptor antagonist has following formula:

The radicals R of general formula ₁, R ₂, R ₃, R ₄And R ₅Be independent the definition.R ₁Be H, alkyl, assorted alkyl, aryl, heteroaryl, C (O) OR ₆Or C (O) R ₆R ₂Be H, alkyl, assorted alkyl, aryl, heteroaryl, C (O) OR ₆Or C (O) R ₆R ₃Be H, alkyl, assorted alkyl, aryl, or heteroaryl.R ₄Be H, alkyl, assorted alkyl, aryl or heteroaryl.R ₅Be OR ₇, alkyl-OR ₇Or assorted alkyl-OR ₇R ₆Be alkyl, assorted alkyl, aryl or heteroaryl.R ₇Be NO ₂, C (O) R ₆, C (O) alkyl-NO ₂Or the assorted alkyl-ONO of C (O) ₂Following substituent group is preferred: R ₁And R ₂Be H; R ₃And R ₄Be H or alkyl; R ₇Be NO ₂Or C (O) alkyl-ONO ₂

Preferably, R ₁Be H, R ₂Be H, C (O) O-alkyl or C (O) O-aryl.R wherein ₂Be C (O) O-alkyl, preferably, alkyl group is a methyl, ethyl, N-propyl group, isopropyl, N-butyl, sec-butyl, the tert-butyl group, or phenyl.R wherein ₂Be C (O) O-aryl, preferably, aromatic yl group is a phenyl, or substituted-phenyl.More preferably, R ₁And R ₂Be H.

Preferably, R ₃And R ₄Be H or linear alkyl group.R wherein ₃And R ₄Be alkyl group, preferably, group is a methyl, ethyl, N-propyl group, N butyl, sec butyl, the tert-butyl group, or phenyl.

Preferably, R ₅Be ONO ₂, O-alkyl-ONO ₂Or OC (O)-alkyl-ONO ₂Work as R ₅Be O-alkyl-ONO ₂, preferably, alkyl group is CH ₂, CH ₂CH ₂Or CH ₂CH ₂CH ₂Work as R ₅Be OC (O)-alkyl-ONO ₂, preferably, alkyl group is CH ₂, CH ₂CH ₂, CH ₂CH ₂CH ₂, or CH ₂CH ₂CH ₂CH ₂More preferably, R ₅Be ONO ₂

Nmda receptor antagonist chemical compound of the present invention is to begin synthetic from the halogen adamantane derivative.The halogen adamantane derivative is with acid and the existing amide adamantane derivative of acetonitrile treatment.The nmda receptor antagonist chemical compound of functionalization is provided with acid and second agent treated nmda receptor adamantane compound.

In some cases, second reagent that is used to form the nmda receptor antagonist chemical compound of functionalization is water.The chemical compound of Xing Chenging is an amino alcohol in this case.Amino alcohol also is nitratedly to provide amino nitric acid derivant or hydrolysis that aminoalcohol derivative is provided.When forming amino alcohol, various steps can be utilized the nmda receptor antagonist chemical compound of making other, comprise following unrestricted example: the 1) protection of amine groups, and then the protection of going of the nitrated and amine groups of alcohol groups provides amino nitric acid derivant; 2) protection of amine groups, then the protection of going of the esterification of alcohol groups and amine groups provides amino ester derivative; With 3) protection of amine groups, then provide carbarnate nitric acid-ester derivant with esterification of halogen hydrochloric acid and nucleophilic displacement of fluorine.

In other situation, second reagent that is used to form the nmda receptor antagonist chemical compound of functionalization is formic acid.The chemical compound of Xing Chenging is a propylhomoserin in this case.Propylhomoserin is regulated and is formed ammonia A Er Kano.Ammonia A Er Kano is nitrated to provide ammonia alkane nitric acid derivant, or goes protection that ammonia A Er Kano derivant is provided.When ammonia A Er Kano derivant formed, amine groups had been protected formation ammonia A Er Kano derivant, the nitrated subsequently ammonia alkane nitric acid derivant that provides.Go protection that amino alkane nitric acid derivant is provided amine groups.

Fig. 1 has shown the synthetic of ammonia nitric acid derivant.Chemical compound 1, dimethyl-bromo-diamantane (obsolete) provides dimethylamino chemical compound 2 with sulphuric acid and acetonitrile treatment.Amide 2 is and the reaction of sulphuric acid and water, and amino alcohol 3 is provided, and utilizes the nitrated formation chemical compound 8 of nitric acid and acetic anhydride.

Fig. 1 has also shown the synthetic of amino nitric acid derivant.Chemical compound 3 is de-protected with sodium hydroxide, and amino alcohol 4 is provided.The amine groups of chemical compound 4 forms carbamate alcohol 5 with (BOC) 2O protection.Carbamate 5 usefulness nitric acid and acetic anhydride are nitrated, and itrated compound 6 is provided, and go protection to form amino nitrate hydrochlorate 7 with the salt acid treatment.

Fig. 2 has shown the synthetic of amino ester derivative.Amino alcohol 9 is to work as the thing alkylation with the grade of benzyl bromide a-bromotoluene, and the amino alcohol 10 of protection is provided.Chemical compound 10 acetylations produce ester 11.Ester 11 carries out hydrogenation, and acidify provides amino alcohol hydrochlorate 12 then.

Fig. 3 has shown the synthetic of carbamate nitric acid-ester derivant.Amino alcohol 9 is being used (PhCH ₂OCO) ₂Protection had produced carbamate 13 when O handled.Carbamate 13 usefulness halogen alkyl hydrochloric acid esterifications provide chemical compound 14, carry out nucleophilic displacement of fluorine with silver nitrate, have produced carbamate nitrate 15.

Fig. 4 has shown the synthetic of aminoalkyl-nitric acid derivant.Amide 2 is to form amino acid/11 6 with sulphuric acid and formic acid reaction.Chemical compound 16 usefulness triethylamines and ethyl chloride formic acid are handled provides blended anhydride, then produces ammonia A Er Kano 17 with the sodium borohydride reaction.Produce aminoalkyl-nitrate 22 with nitric acid and acetic acid hydrogen nitrated 17.

Fig. 4 has also shown the synthetic of aminoalkyl nitric acid derivant.Ammonia A Er Kano 17 usefulness sodium hydroxide go protection, and provide 18 with the acetic acid acidify.The amine groups of chemical compound 18 is protected after reacting with N phenyloxycarbonyl oxygen base butanimide, forms carbamate 19, uses the nitrated generation carbamic acid of nitric acid and acetic anhydride ester alkyl-nitrate 20 subsequently.The carbamate 20 usefulness hydrobromic acid and the acetic acid treatment of chemical compound 20 provide aminoalkyl-nitrate 21.

It is amine or the synthetic preferred intermediate product of aminoalkyl-nitric acid derivant that chemical compound lot is arranged.Such chemical compound comprises propylhomoserin 16, ammonia A Er Kano 17 and amino alcohol hydrochlorate 18.

Chemical compound of the present invention and compositions can be used to make many neuropsychiatric disorders of pharmaceutical treatment and morbid state, as damage ischemia or the anoxia symptom comprises shock, hypoglycemia, cerebrum ischemia, cardiac shock, spinal cord injury, head damage, enclose living phase anoxia, cardiac shock and hypoglycemia neuronal damage.Nerve degeneration is disorderly as epilepsy, the Alzeimer disease, and the Huntington disease, parkinson disease and the sclerosis of amyotrophy rear side also can be treated.Can comprise by other neuropsychopathy diseases or the disorder that this chemical compound of administration and compositions are alleviated, be not limited to as follows: depression, bipolar disorder, anxiety, faint from fear pain, schizophrenia, muscle spasm, migraine, urinary incontinence, narcotic withdrawal, opiate tolerance and withdrawal, vomiting, cerebral edema, the tardy dyskinesia, the inductive dementia of AIDS, ocular injury, retinopathy, cognitive disorders and infects relevant neuronal damage as in cognition with HIV, move and consciousness in functional disorder.

The experiment of therapeutic effect

In the treatment neuropsychiatric disorders, determine that the experiment and the storage of therapeutic effect usually can be at the terminal and the statistic handbooks of abalienation, the 4th edition, find in the sick publishing house of Americanism (1994).As serum or CSF blood plasma glutamic acid level, MRS, MRI and PET provide definite effect of using the scheme of nmda receptor antagonist compounds for treating in conjunction with experiment more specifically for patient's experiment and mensuration.These mensuration can be in conjunction with other principles, be the increase or the minimizing of body weight, obtain or keep the ability of occupation, the respond of social circumstance, and the storage of more main body, as the behavior that medicine is thirsted for, the increase or the minimizing of the many or energy of Libiee, measure with the generality of health, so that obtain the analysis that patient more completely replys treatment.

CSF (brain notochord liquid) and the blood plasma level of glutamic acid in depressed patient

Can measure by the minimizing of test blood plasma and marrowbrain liquid two-story valley propylhomoserin or glutamic acid level from the therapeutic effect that is used to regulate the active chemical compound of nmda receptor.The glutamic acid blood plasma level is known be in depressed patient than colony matched group higher (referring to, Kim et al., 1982; Mathis et al., 1988, Mauri et al. (1998) and Berket al., (2000), and Livine et al., (2000) and Castillo et al., (2000), these documents are all by being incorporated in this paper in this citation.Though Memantine hydrochloride does not stop the release of glutamic acid, have only glutamic acid that its nmda receptor is worked, promptly the glutamic acid level still improves, but Memantine hydrochloride can stop the effect of the glutamic acid of raising simply.But because Memantine hydrochloride will stop cell death, so release glutamate in this way undesiredly, blood plasma and CSF glutamic acid level are often replied patient's treatment and are descended.

Patient evaluation:

Effectiveness with the treatment of nmda receptor antagonist also can be determined with one or several clauses and subclauses described below of administration.Raising in patient's score usually with weaken pathological state and to improve the neuropsychopathy state relevant.

MADRS (Montgomery and Asberg, 1979, the document is all by being incorporated in this paper in this citation) be 10 instruments that are used to assess adult's depressive symptom and assess any change of these symptoms.The reliability of the Inter-rater of scale is high, and score is relevant with HAMD (as this paper discussion) obviously.In 10 each is in the scale of 0-6, and every has different narrations.The score of this each project adds and forms total score together, and scope was at 0 to 60 minute.The raising of the score in the patient shows greater than 5% behind administration NMDA antagonist chemical compound, and the pathological factor of neuropsychiatric disorders descends, and the raising of patient's score 10% shows and reaches therapeutic effect after with the therapeutic scheme of chemical compound.

HAMD (Hamilton, 1960, simultaneously referring to, de Montigni et al., 1999; Versiani et al., 2000; Shelton et al., 2001, these documents are all by being incorporated in this paper in this citation) be the mensuration of the observation ratio of the extensive depressed seriousness of utilizing.21 the observation of this scale (HAMD) is to assess depressed seriousness and its improvement in therapeutic process.It has been assessed the existence and the seriousness of individual signal and has not been had the symptom of the depression of psychotic features.Total score is 21 a sum, and scope is at 0-65.Patient's improvement obtains after giving NMDA antagonist chemical compound the decline that shown the pathological factor of neuropsychiatric disorders greater than 5%, and shows in the raising with patient's score of 10% of the therapeutic scheme of this chemical compound and to have reached therapeutic effect.

The CORE assessment (Parker and Hadzi-Pavlovic, 1996) that psychomotor changes is to have comprised 18 signals (observable feature), and these calculate the back clinician that seeks medical advice.Each signal calculates (0-3) 4 scales.The subbreed row of the total of these projects have produced the score on the three-dimensional of finding, have listed the variation of psychomotor: non-reacted, and retardance and exciting.Can be used to specify patient's black gallbladder or non-black gallbladder hypotype from total score of each project.The assessment that the psychomotor of CORE changes is not the measure of diagnosis.When the diagnosis of initial depression is carried out, it is a hypotype system to be utilized, and separately black gallbladder is to non-black gallbladder type.Show decline is arranged in the paathogenic factor of morbid state in variation from black gallbladder hypotype to the branch apoplexy due to endogenous wind of non-black gallbladder hypotype.

It is the extensively observation calculating measure of the anxiety seriousness of utilization that the psychosis of Hamilton anxiety is calculated scale (HAM-A).Comprise 14 projects in the scale.Each project is to calculate on the scale of 0-4.This scale is seriousness and its improvement in the process of treatment that is used to assess anxiety.The HAM-A PTS is the sum of 14 projects and obtaining of scope 0 to 56.Behind administration NMDA antagonist chemical compound, the raising of patient's score shows in the paathogenic factor of neuropsychiatric disorders decline is arranged greater than 5%.And the raising of patient's score 10% shows after with the therapeutic scheme of chemical compound, has reached the therapeutic effect in the treatment anxiety.

YMRS (Young et al., 1978, the document is by being incorporated in this paper in this citation) comprises 11 projects.Project 5,6,8 and 9 calculated to 8 (symptom is very serious) in 0 (symptom does not exist).Remaining project is calculated to 4 (symptom is very serious) from 0 (symptom does not exist) in scale.Project 5,6,8 and 9 (excitement, speech include and the radical behavior of the property upset) give the twice of remaining 7 weight, so that compensation serious disease patient's bad symptom.The YMRS PTS is in the 0-60 scope, and is initial efficacy parameter.Super manic/manic symptoms that the YMRS scale that obtains should develop in treatment.Behind administration NMDA antagonist chemical compound, shown the decline of the paathogenic factor of neuropsychiatric disorders, and shown in 10% raising and to have reached therapeutic effect with the patient's score behind the therapeutic scheme of this chemical compound greater than the raising in patient's score of 5%.

PANSS calculate originate from conventional, the half hitch structure, 30-40 minute clinical sought medical advice and the source of other information.30 projects in PANSS are (1=do not have, and 7=very) of calculating on 7 scale.7 projects be combined to form positive scale, be evaluated at the feature that has in the schizophrenia, these features are non-existent among the patient in the normal mental status.Form negative scale in 7 projects in addition, be evaluated at the feature that does not have in the schizophrenia, but the feature that exists among the patient of normal condition.According to the difference between these scales, bipolar combination scale is specific to the advantage of a symptom to other symptoms.At last, the 4th index, general psychology scale of causing a disease has been stipulated the seriousness of whole disorder by the sum of all the other 16 projects.Three offset items have been assessed radical danger.PANSS calculates the method that assess patient right psychotic symptom in therapeutic process is provided.Psychotic symptom has reported it is that utilization with the NMDA antagonist takes place, and any chemical compound of regulating glutamic acid neurotransmission approach should be assessed the tendency of its development psychotic symptoms.

CGI scale (national psychosis health research institute, 1976, the document is all crossed in this citation and is incorporated in this paper) is the scale of the insane treatment of assessment three projects of replying.Time of administration is 5 minutes.This scale comprises three projects: the seriousness of the state of an illness (project 1); The whole world improve (project 2); And efficiency index (project 3).Project 1 is (1=is normal, and 7=is in the most serious patient) that calculates on the scale of 7 points; In project 2 (1=improves very much, and 7=is very bad).Each comprise non-assessment other reply.Project 3 is (never the arriving over-drastic therapeutic effect) of calculating on the scale of 4

points.Project

1 and 3 is to assess according to the treatment in the week of front.Project 2 is to assess from the period that begins present treatment.Raising greater than patient's score of 5% behind administration NMDA antagonist chemical compound shows in the paathogenic factor of neuropsychiatric disorders decline is arranged, and patient's score has 10% raising to show to have reached therapeutic effect after with the therapeutic scheme of chemical compound.

Nuclear magnetic resonance spectroscopy

The more experimental data of replying the patient of treatment can obtain by nuclear magnetic resonance spectroscopy and PET.Neuronal damage is relevant with N-acetyl-aspartic acid (NAA) peak of for example decline on MR spectrum.The chemistry of this type move change can be in the process of patient treatment after so that detect the development of neuropsychiatric disorders, and the preparation dosage.

(GE Signa/Horizon5.6 Milwaukee) carries out quantitative single voxel[to utilize 3.0T clinical scanning instrument ¹H]-the MRS experiment.Utilize the acquisition parameter of project, the Echo Acquisition Mode (STEAM) that the stimulates sequence of beating is used to reach spectrum, the state of an illness also comprises unprohibited water reference scan, it is quantitative to be used for metabolism: ET 30msec, regulate time 13.7msec, repetition time 2sec, the circulation mutually of 8 steps, 2048 points, spectral width 2500Hz, 128 about 5 minutes average total acquisition times.Pedigree will be from volume, and temporo obtains in the zone (ROI) that the 8cc in the pallette of cranium and occipital bone needs.Short echo [ ¹H]-the MRS human brain in compounds identified research comprise the neuron labelling, N acetyl aspartic acid (NAA), glutamine/GABA (Glx), creatine/phosphagen (Cr), compound choline (Cho) and inositol (ml).Zone under each resonance is proportional with special neuro chemistry compound concentrations.The decline of replying in the paathogenic factor of Memantine hydrochloride administration at neuropsychiatric disorders causes for example increase at NAA peak, has shown the improvement of neuronal function.

Utilize and analyse software timing separation, the zone at indivedual peaks meets.Each compound concentrations is reported in arbitrarily ⁴/ water) proportional.This water reference method has been used for this area 10 years, and the state of an illness is effective in many seminar.Analysis software is the information (http://carbon.uab.es/mruiwww) in known field and has eliminated the subjectivity in the definite spectrum peak zone in the most older method.In brief, software has carried out the meeting automatically of water peak of little prevention, determines its zone, peak, and has also utilized using mutually and the automatically zero in proper order attitude relevant with metabolite data of water peak.After this, user has entered the information about the front of metabolite data, so that obtain the software initial value of its matching process.The chemistry that the information that obtains previously is included in the expection of each the main chemical compound that occurs in the typical proton brain map moves change and the definite start line width of corresponding waterline width.The chemistry that gives program moves variate and is based on literature value, and wherein NAA is 2.02ppm, and the Glx complex is 2.3ppm, and Cr is 3.03ppm, and Cho is 3.22, and mI is 3.56.Under these input data, software meets the metabolism collection of illustrative plates with trial then, and with its result visualization with in document, can be with its exchange premium spreadsheet analysis programme.Meet mI reliably in order to reach, Cr and Glx peak that also must meet other at the zone line of mI or the part crossover.Visible and quantitative results is as good meeting and acceptable or multiple once more improvement.Most of collection of illustrative plates (about 80%) only needs 1 repeat to reach with most of other and repeat meeting of the successful satisfactions in back at 2 times.If all the other show the noise of the not structure of advantage, it is acceptable meeting so.The zone of water peak and metabolic peak enters spreadsheet.The data of each metabolic peak increase doubly 10,000 (in the heart report factor) easily then, are divided into the zone, brain water peak of not checking then.Quantitatively metabolite concentration is reported into arbitrary unit (* 10 ⁴)/water.Water and metabolism releasing effect are irrelevant with this technology, because these values that each patient is obtained will be time restricted (Measuring Time will be gone to other 2 hours of each experimenter).Utilized the acquisition parameter, reduced because the uncertainty that the neuro chemistry concentration that relaxing effect produces is estimated.Say that specifically the ET of the weak point of 30msec has reduced the destruction of T2 signal, the T1 mistake that produces of the collection of illustrative plates of the collection when lax fully that the standard of 2sec has repeated time decreased.This is the common trade-off in the clinical setting.

PET and depressed functional anatomy: the meaning that glutamic acid can transmit

Depressed experimenter's the PET imaging research of suffering from MDD and BPD is verified, and regional cerebrum blood stream (CBF) and glucose metabolism are abnormal, show that glutamic acid energy delivery areas may be abnormal in depression.Reflection glutamic acid in glucose metabolism signal (closely relevant with CBF in physiology activation process) advantage ground can transmit (Magistretti et al., 1995).In the subgroup of depression, the abnormality of consistent mode has appearred in the nerve circulation of tangling in the motion of the experimental evidence of other types development.Specifically say, adult's depressed psychic trauma be with at lower limb zones amygdala, before abdomen, the cingulum cortex is relevant with the glucose metabolism that inferior cortex zone promotes with cortex, and there is anatomical relationship widely in these these regional and following zones, as preceding Reil's island, orbital cortex, back band, middle level thalamus, striped (referring to Drevets, 2000) with abdomen.

The active specificity of lower limb-thalamus-cortex (LTC) that promotes

Tonsil and and preceding cingulum in metabolism replying in the drowsiness MDD subgroup and promoting undesiredly.The medical science that recurs in the process that lacks 5-hydroxy tryptamine, the MDD experimenter of Tui Huaing has the tonsil and the orbital cortex metabolism of higher benchmark usually than those that do not recur again.Other researchs of the depressive patient of not seeking medical advice of patient MDD also have been reported in the orbital cortex have compared CBF and the metabolism that raising is arranged with normal healthy controls, the longitudinal study of the depressive patient of imaging as one man shows before and after treatment, at effective anti depressant medication, ECT, the light treatment, after multiple transcranial magnetic stimulates (rTMS) and forfeiture sleep, CBF and metabolism are at orbital cortex, PFC in the abdomen, progenesis and and end body ACC and preceding Reil's island in metabolism descend (referring to Drevets et al., 1999, Drevets, 1999, these documents are all by being incorporated in this paper in this citation).The treatment of Memantine hydrochloride is replied can be by at benchmark, and the lower limb-thalamus-cortex activity of the lifting in the depressed symptom of not seeking medical advice is predicted.Such assessment allows the inferior Phenotype of identification of M DD, as if more resembles the treatment that has benefited from the chemical compound that can transmit with reduction glutamic acid.

Start patient scan

The preparation of main body comprises insertion of catheter into vein.PET scanning is (thin slice of 35 vicinities, the separation of 4.25mm platform that utilizes GEAdvance to reach; 3D differentiates 6 to 7mm FWHM, and 3D obtains mode).Initial divergent scan mode obtains in heart, so the experimenter moves to the scanner of whole health from foot.At first, on breast, reach 2 minutes transmission scan, utilized ⁶⁸Ge/ ⁶⁸The rotating rod of Ga, the electronic window rod that unrolls makes the scanner minimum.This one scan is built into immediately again and instructs the platform that relocates scanner, so that it is centered close to heart.After relocating the experimenter, obtain about 8 minutes transmission scan, be used to reduce the correction of following the trail of absorption cardiac in period divergent scan mode.Behind this transmission scan, by group injection (2 minutes) slowly give 4.5mCi [ ¹⁸F] fluorodeoxyglucose (FDG).After 35 minutes long kinetics 2D of framework acquisition in 10 * 30 seconds disperses scanning, with 10 * 3 minutes framework.

After this one scan, the experimenter gets up from the bed of scanner, how, bed will be installed the headstock.The experimenter navigates to scanner with head, and head is fixed with the thermoplastic materials cover, in the position of a plurality of surperficial fixing head (for example, forehead, temporo and back head surface, blade of a sword bone), to reduce possible motion.When closing eyes rest carrying out brain, the experimenter disperses scanning.Carry out 2 minutes transmission scan, make up again immediately, so that the initial structure that needs is positioned the center in the visual field approximately.Carry out transmitting for the second time the correction that scanning (8 minutes) reduces separate data.Inject 10 minutes divergent scan mode of startup in back 45 minutes at FDG.Inject the venous blood sampling of carrying out 5 minutes intervals in back 45 minutes at FDG.Calculate the radioactive activity of blood plasma and whole blood.Also obtain three vein samples, measured plasma glucose.

Utilize identical method to treat back scanning.By arranging laser rays the experimenter is positioned in the scanner, laser rays come in the comfortable beginning scanning process with hard thermoplastic materials cover on scanner platform on the labelling so that a position is near all frameworks.

Abdomen stricture of vagina in the assessment PET imaging

Concern that with the spatial discrimination of PET the research of the important area of less depression is the abdomen stricture of vagina, it comprises that nuclear is according to volt.In primates, have according to those of the connective tissue of volt and the cell of histochemistry feature and NAV and the interior tail of abdomen and mix, so that nuclear lacks tangible microcosmic and macroscopic border (Heimer and Alheid, 1991, these documents are all by being incorporated in this paper in this citation) according to volt.This striatal preabdomen branch (AVS) is what to be tangled in the stimulation of the developing tonsil of back relation and motion and socket of the eye and inboard PFB, and the back tail is breathed out the back according to lying prostrate the relation of importing into (Everitt et al., 1989 of having accepted at first from the cortex zone that participates in sensorimotor function; Haber et al., 1995; Ongur and Price, 2000; Selemon and Goldman-Rakic, 1985, these documents are all by being incorporated in this paper in this citation).

Purpose in front is to understand motion and breathes out in the PET research of dopamine (DA) D2/D3 receptors bind of the relation of abdomen stricture of vagina DA between discharging, the PET measurement of the variation in the endogenous DA in dexamfetamine (AMPH) back is to reply relevant (Drevets et al. with the relevant enjoyment that the people strides in the subprovince of stricture of vagina, 1999,2001).Health volunteer AMPH injection (0.3mg/kg i.v.) before and obtain afterwards [ ¹¹C] show with PET measurements of the raclopride specific bond of DA D2/D3 receptor, AMPH inductive in conjunction with the variation in the potentiality (δ BP) in AVS but be not to be significantly [to comprise that according to Fu Qu tail in the abdomen is breathed out preceding abdomen stricture of vagina in the back of the body tail; P＜0.005] (DCA:t=45).DeltaBP in AVS is greater than DCA[p＜0.05] breathe out the middle part tail (MCA; P＜0.01) in, and similar in appearance in the abdomen stricture of vagina (VPU).Variation in euphoria calculates and AVS (r=-0.95, p=0.001) in, but be not that (r=+0.30, n.s) the delta BP in is correlated with at DCA.Difference between these coefficient of relationship is tangible (p＜0.001).Variation among the euphoria and VPU[r=-0.77; P＜0.05] in but be not at DPU (r=+0.25), MCA (r=-0.61), or the delta BP in the whole stricture of vagina (r=-0.50) is relevant.

Because the restricted quarter of PET is differentiated, area measure is the influence (Links et al., 1996) that is subjected to the radioactive activity that the surrounding tissue in contiguous structure breathes out to overflow in the dilution effect.The measuring-signal of breathing out AVS from DCA is to distinguish easily, but AVS breathes out abdomen nuclear result's relation faint (Drevets et al., 1999).This has reflected that the littler separate front and back of breathing out to examine with the proportional AVS of horizontal resolution compares, and axial scanner is differentiated proportional AVS and is breathed out axial separation between the DCA (7 to 12 millimeters of philtrums) bigger (for example, average A VS volume is 2.77 ± 0.722ml in the people; Drevets et al., 2001).The volume resolution that 1.25mm point radioactive activity is originated in Siemens HR+ (similar in appearance to GE Advance) has 5.3mm the FWHM axial and measurement that 6.6mm is horizontal to be distinguished, and has produced the volume difference of 0.23mL.8.3% (2.77 ± 0.722ml) of the average A VS volume that this volume is just measured in from the MRI imaging among the healthy people.5.3mmFWHM axial difference mean and be positioned will in fact the PET measurement from AVS not had effect from the pixel of AVS edge more than 11 millimeters.AVS breathes out DCA and breathes out that the separation of center to center is good between the DPU on this distance.So in the people, those of breathing out DPU with DCA easily from the measuring-signal of AVS are distinguished, and will seldom be subjected to influence from those of VPU and MCA.

Metabolic activity before in depression in the abdomen stricture of vagina

So, it is bigger in than DCA in AVS that the different regional metabolic abnormality of proof of striding the territory, subprovince in present research depends on the mean difference that shows in two groups, and this difference can not with among MCA or the VPU in addition bigger difference (Drevets et al. is described, 1999,2001).Be evaluated at center (Fox et al., 1986 of the purposes of the PET among the voxel that the energy of striding than the relative different of the radioactivity tracer concentration of the symptom among the still less isolating ROI of FWHM difference is the location maximum difference in the collection of illustrative plates research in brain; Friston et al., 1996, these documents are all by being incorporated in this paper in this citation).

ROI based on MRI analyzes the glucose metabolism that can be used for being evaluated at these striped subprovinces between one pole depression and the normal healthy controls.In contrast, be used for that PET camera that the scope of coefficient (SD/ is average) of difference of the glucose metabolism of regular AVS breathes out to distinguish as the similar sensitivity with present project measures, be 6-7%.In depressed individuality, the comparative control individuality is at AVS (p＜0.05) but be not at MCA, DPU, among DCA or the VPU in the scope of this 6-7% regional glucose metabolism increase.Change list in regional glucose metabolism is understood therapeutic effect, and promptly the decline of the variation of 6-7% has shown therapeutic effect in the regional glucose metabolism in the patient.

Embodiment 1:1-acetaldehyde amino-3,5-dimethyl-7-hydroxyadamantane (3)

At 0 ℃, in nitrogen,, add oleum (3ml) in the 5-dimethyladamantane (0.2g), 0 ℃ of stirred reaction mixture 1 hour at 1-acetaldehyde amino-3.Reactant mixture is poured on ice (10g), with ether (10ml * 4) extraction product.Breathe out ethereal solution after water (10ml) washing merges with saline (10ml).Use dried over sodium sulfate solution.Remove in a vacuum and desolvate, after stopping crystallization, obtain the 70mg white product.Obtain pure product by recrystallize in ether. ¹H?NMR(DMSO-d ₆，ppm)：730(brs，1H，NH)，4.37(brs，1H，OH)，1.72(s，3H，COCH ₃)，1.65(s，2H)，1.47(s，4H)，1.24-1.14(dd，4H，J＝11.2，23.9Hz)，0.99(s，2H)，0.82(s，6H，2×CH3).M.p.194-195℃.Anal.(C ₁₄H23NO2)，C.H.N.

Embodiment 2.1-amino-3,5-dimethyl-7-

Synthesizing of hydroxyadamantane hydrochloric acid (4)

1-acetaldehyde amino-3,5-dimethyl-7-hydroxyadamantane (0.4g) and NaOH (1.1g) add in the diethylene glycol (7ml), reactant mixture are heated to 175 ℃, 15 hours.At room temperature after the cooling, add ice (10g), with ether extraction product (10ml * 4).Breathe out the ethereal solution that water (10ml) washing merges with saline (10ml).Use dried over sodium sulfate solution.Remove in a vacuum and desolvate, when stopping, after the crystallization, obtain the 250mg white product.Add the HCl in the ethyl acetate, convert free alkali to HCl salt. ¹HNMR(DMSO-d ₆，ppm)：8.12(brs，2H，NH)，4.72(brs，1H，OH)，1.58(s，2H)，1.40-1.31(dd，4H，J＝12.3，21.6Hz)，1.23(s，4H)，1.08-0.98(dd，2H，J＝12.6，23.3Hz)，0.88(s，6H，2×CH3).M.p.28?1-282℃.Anal.(C ₁₂H22NOCI+0.5H2O)，C.H.N.

Embodiment 3:1-tert-butyl carbamate-3,5-

Synthesizing of dimethyl-7-hydroxyadamantane (5)

1-amino-3,5-dimethyl-7-hydroxyadamantane (100mg) is dissolved in the oxolane (2ml).Add triethylamine (180ml) subsequently, two-tert-butyl, two carbonate (336mg) and dimethyl aminopyridine (2mg).Stirring at room reactant mixture 2 hours, any adding 0.5N NaOH (2ml).Stirred reaction mixture spends the night.Remove triethylamine in a vacuum, add ether.With 0.1N HCl and salt water washing ethereal solution.Use dried over sodium sulfate solution.Remove in a vacuum and desolvate, in ether, obtain the 60mg product after the stop crystallization. ¹H?NMR(DMSO-d ₆，ppm)：6.35(brs，1H，NH)，4.35(brs，1H，OH)，1.59(S，2H)，1.40(s，4H)，1.35(s，9H，3×CH3)，1.22-1.13(dd，4H，J＝11.1，20.6Hz)，0.99(s，2H)，0.82(s，6H，2×CH3).

Embodiment 4:1-tert-butyl carbonate-3, the 5-dimethyl-

Synthesizing of 7-nitric acid diamantane (obsolete) (6)

At 0 ℃, in the nitrogen, will (1: 1.5/v: the ethyl nitric acid (0.08ml) of the cooling of mixture v) (0 ℃) joins 1-tert-butyl carbonate-3 from be fuming nitric acid and acetic anhydride, in dichloromethane (1ml) solution of 5-dimethyl-7-hydroxyadamantane (40mg), 0 ℃ of stirred reaction mixture 15 minutes.Add 1N sodium bicarbonate solution (5ml), with dichloromethane (10ml) extraction product.Water (10ml * 3) washing dichloromethane solution.Use dried over sodium sulfate solution.Remove in a vacuum and desolvate, obtain oily product (30mg). ¹HNMR(DMSO-d ₆，ppm)：6.66(brs，1H，NH)，2.14(s，2H)，1.70(s，2H)，1.69(s，2H)，1.63-1.60(d，2H，J＝12.3Hz)，1.46-1.43(d，2H，3＝12.2Hz)，1.36(s，9H，3×CH3)，1.17-1.08(dd，2H，111.4，22.6Hz)，0.91(s，6H，2×CH3)。Calculate C ₁₇H ₂₈N ₂O ₅The high-resolution MS:363 of Na (MS+Na).1895。Found?363.1908。

Embodiment 5:1-amino-3,5-dimethyl-7-

Synthesizing of nitric acid diamantane (obsolete) hydrochlorate (7)

At 1 tert-butyl group carbonate-3, add ethyl acetate (the 3N HCl among the 0.5ml in 5-dimethyl-7-nitric acid diamantane (obsolete) (40mg).At room temperature stirred reaction mixture is 30 minutes.Filtering-depositing is used the ether washed product.Obtain pure white product (35mg). ¹HNMR(DMSO-d ₆，ppm)： 8.36(brs，2H，NH)，2.15(s，2H)，1.69(s，4H)，1.57-1.44(dd，4H，J＝12.2，32.8Hz)，1.26-1.10(dd，2H，3＝1.12.0，44.3Hz)，0.96(s，6H，2×CH3).m.p.225-226℃.MS(MS+H ⁺)：241.Anal.(C12H21N2O3CI).C.H.N.

Embodiment 6:1-acetaldehyde amino-3,5-dimethyl-7-

Synthesizing of nitric acid diamantane (obsolete) (8)

In 0 ℃ of nitrogen, in acetic anhydride (0.3ml), add nitric acid (0.2ml).At 0 ℃, after stirring 5 minutes, add 1-acetaldehyde amino-3,5-dimethyl-7-hydroxyadamantane (50mg) was 0 ℃ of stirred reaction mixture 1 hour.In the sodium bicarbonate solution (20ml) of the 1N that reactant mixture is poured at cold (0 ℃), with ether extraction product (10ml).Wash ethereal solution (10ml * 3) with water.Use dried over sodium sulfate solution.Remove in a vacuum and desolvate, obtain the product of 31mg. ¹HNMR(DMSO-d ₆，ppm)：7.52(brs，1H，NB)，2.23(s，2H)，1.73-1.66(m，9H，COCH3，3×CH2)，1.51-1.47(m，2H)，1.15-1.13(m，2H)，0.92(s，6H，2×CH3).m.p.152-153℃。Anal.(C14H22N2O4)，C.H.N.

Embodiment 7:1,1-diphenyl amino-3, the 5-dimethyl-

Synthesizing of 7-hydroxyl-diamantane (obsolete) (10)

Add benzene bromine (0.16ml) in the 1-amino-3 in DMF (2ml), 5-dimethyl-7-hydroxyadamantane hydrochlorate (100mg) and breathe out sodium carbonate (200mg).The stirred overnight reactant mixture.With dichloromethane (10ml) extraction product, water (20ml * 2) washing.Use the dried over sodium sulfate organic facies, remove in a vacuum and desolvate.By flicker column chromatography eluting, (1/2, v/v) purified product obtains 124mg white solid (76% output) with ethyl acetate isohexane. ¹HNMR(DMSO-d ₆，ppm)：7.31-7.04(m，10H，2×C6H5)，4.32(1H，OH)，3.71(s，4H，2×C6H5CH2)，1.44(s，2H)，1.35-1.27(m，4H)，1.22-1.13(dd，4H，J＝11.8，21.2Hz)，0.97(s，2H)，0.81(s，6H，2×CH3)。

Embodiment 8:1-amino-3,5-dimethyl-7-

Synthesizing of acetate diamantane (obsolete) hydrochlorate (12)

In DMF (0.4ml) 1,1-diphenyl amino-3 adds dichloromethane (2ml) in 5-dimethyl-7-hydroxyadamantane (50mg) solution.In nitrogen, add chloroacetic chloride (1ml) at 0 ℃, stirred overnight reactant mixture 5 times.Add saturated sodium carbonate liquor (5ml).With dichloromethane (10ml) extraction product and wash (20ml * 2) with water.With the dried over sodium sulfate organic facies and in a vacuum except that desolvating.Do not need to be further purified lysate in methanol (10ml).Adding Pd/C (10%, 10mg), at 40LB/inch ²Pressure under the hydrogenation mixture that spends the night.Filtering mixt removes and desolvates.Add the HCI in the ethyl acetate, filtering-depositing is used the hexane wash solid, obtains the product of 15mg behind air drying. ¹H?NivIR(DMSO-d ₆，ppm)：8.30(brs，2H，NH ₂)，2.09(s，2H)，1.93(s，2H)，1.93(s，3H，COCH3)，1.72-1.63(dd，4H，J＝12.6，21.4Hz)，1.50-1.39(dd，4H，J＝11.7，29.6Hz)，1.18-1.05(dd，2H，J＝14.1，36.5Hz)，0.93(s，6H，2×CH3)。

Embodiment 9:1-(phenyloxycarbonyl) amino-3, the 5-dimethyl-

Synthesizing of 7-hydroxyadamantane (13)

1-amino-3 in DMF (5ml) and water (0.3ml) adds diphenyl two carbonic acid (1.41g) and breathes out sodium carbonate (1.3g) in 5-dimethyl-7-hydroxyadamantane hydrochlorate (570mg) solution.The stirred overnight reactant mixture.With t-butyl methyl ether (500ml) extraction product, water (400ml * 2) washing.Use the dried over sodium sulfate organic facies, remove in a vacuum and desolvate.By the flicker chromatography eluant, (1/3, v/v) purified product obtains the 701mg white solid to breathe out hexane with ethyl acetate. ¹HNMR(DMSO-d ₆，ppm)：7.35-7.28(m，5H，C6H5)，6.96(brs，1H，NH)，4.94(s，2H，OCH2)，4.41(1H，OH)，1.62(s，2H)，1.43(s，4H)，1.24-1.14(dd，4H，J＝11.5，22.0Hz)，0.97(s，2H)，0.83(a，6H，2×CH3)。

Embodiment 10:1-(phenyloxycarbonyl) amino-3,5-dimethyl-7-

Synthesizing of (3-bromopropyl carbonyl oxygen base) diamantane (obsolete) (14)

1-(phenoxy group-carbonyl) amino-3 in DMF (0.4ml) adds 4-brombutyl chlorine (0.3ml) in the solution of 5-dimethyl-7-hydroxyadamantane (100mg).At room temperature stirred reaction mixture is 2 hours.By the thin layer chromatography eluting, with ethyl acetate and hexane 91/2, v/v) purified mixture obtains the oily product. ¹HNMR(DMSO-d ₆，ppm)：7.38-7.29(m，5H，C6H5)，7.12(brs，1H，NH)，4.95(s，2H，OCH2)，3.53-3.49(t，2H，3＝6.6Hz.COCH2)，2.36-2.32(t，2H，J＝7.7Hz，CH2Br)，2.10(s，2H)，200-1.96(m，2H，CH2CH2CH2)，1.66(s，4H)，1.59-1.41(dd，4H，J＝11.5，51.7Hz)，91.08-1.07(d，2H，J＝3.8Hz)，0.87(s，6H，2×CH3)。

Embodiment 11:1-(phenyloxycarbonyl) amino-3,5-dimethyl-7-

Synthesizing of (3-nitric acid carbonyl propyl oxygen base) diamantane (obsolete) (15)

1-in acetonitrile (phenyloxycarbonyl) amino-3 adds in the solution of 5-dimethyl-7-(3-bromopropyl carbonyl oxygen base) diamantane (obsolete) in the solution of the silver nitrate in the acetonitrile, darkling the stirred overnight reactant mixture.Use the t-butyl methyl ether extraction product, wash solution with water.With the exsiccant organic facies of sulphuric acid, remove the nitrate compound that dried solvent obtains.

Embodiment 12:1-acetaldehyde amino-3,5-dimethyl-7-carboxylic acid diamantane (obsolete) (16)

Slowly add 1-acetaldehyde amino-3, S-dimethyladamantane (1.0g) in the oleum (15ml) in being as cold as 0 ℃ flask 1 hour period.At 0 ℃ of stirred reaction mixture.Dropwise in 1 hour, add formic acid (3ml) then.Other 2 hours of 0 ℃ of agitating solution.Reactant mixture slowly is poured on ice (100g), vigorous stirring.Filter the precipitation that forms, wash with water and obtain .m.p.261-262 ℃ of purified white solid (0.37g).

Embodiment 13:1-acetaldehyde amino-3,5-dimethyl-7-

Hydroxymethyl diamantane (obsolete) (17)

At 0 ℃, the 1-acetaldehyde amino-3 in THF adds triethylamine (0.80ml) subsequently in the suspension of 5-dimethyl-7-carboxylic acid-diamantane (obsolete) (2.0g) and breathes out second chloro-carbonic acid (0.80ml).Stirred reaction mixture at room temperature in 4 hours.Filter the white precipitate that forms then, wash with THF.In filtrate, add NaBH ₄(2.40g).Dropwise in 1 hour, in solution, add entry (2ml), then add more water (50ml).Under reduced pressure remove organic facies, extract remaining aqueous solution with ethyl acetate (100ml * 3).Remove in a vacuum and desolvate, (1/4, solution crystallization product v/v) obtains white solid (700mg) to utilize ethyl acetate and hexane. ¹HNMR(DMSO-d ₆，ppm)：7.28(s，1H，NH)，4.33(t，1H，OH，J?5.7Hz)，3.02(d，2H，CH2OH，J＝5.7Hz)，1.71(s，3H，COCH3)，1.49(s，6H)，1.07-0.97(m，6H)，0.96(s，6H).m.p.152-153℃。Anal.(C15H25NO2)，C.H.N.

Embodiment 14:1-amino-3,5-dimethyl-7-

Hydroxymethyl diamantane (obsolete) hydrochlorate (18)

1-acetaldehyde amino-3,5-dimethyl-7-hydroxymethyl diamantane (obsolete) (200mg) and sodium hydroxide (540mg) join diethylene glycol (4ml), with reactant mixture in nitrogen, be heated to 175 ℃ 15 hours.At room temperature after the cooling, add ice, with ethyl acetate (10ml * 6) extraction.The extract that water (10ml) and saline (10ml) washing merge is used dried over sodium sulfate.Remove in a vacuum and desolvate.Add the HCI in the ethyl acetate, convert free alkali to HCl salt, and obtain the product of 102mg. ¹HNMR(DMSO-d ₆，ppm)：8.19(brs，2H)，4.54-4.51(t，1H，OH，J＝5.0Hz)，3。07-3。05(d，2H，OCH2.J＝4.6Hz)，1.42-1.40(m，6H)，1.01-0.99(M，6H)，0.86(s，6H).Anal.(C13H24NOCl+0.4HCl)，C.H.N.

Embodiment 15:1-(phenyloxycarbonyl) amino-3, the 5-dimethyl-

7-hydroxymethyl diamantane (obsolete) (19)

At the 1-amino-3 of THF (3ml), add N-(phenoxy group carbonyl oxygen base)-butanimide (74mg), at room temperature stirred overnight mixture in the solution of 5-dimethyl-7-hydroxymethyl diamantane (obsolete) (60mg).Remove THF, residue is dissolved in ethyl acetate.Water is breathed out the saline wash solution.By thin layer chromatography, (1: 4, v/v) purified product obtained white solid (80mg) to use ethyl acetate and hexane. ¹HNMR(DMSO-d ₆，ppm)：7.33(m，5H，C6H5)，6.89(brs，1H，NH)，4.94(s，2H，OCH2)，4.32(t，1H，OH，J＝5.7Hz)，3.04(d，2H，CH2OH，J＝5.7Hz)，1.46(dd，6H)，1.04(dd，6H)，0.84(s，6H，2×CH3)。

Embodiment 16:1-(phenyloxycarbonyl) amino-3, the 5-dimethyl-

7-nitric acid methyl-diamantane (obsolete) (20)

1-(phenyloxycarbonyl) amino-3 in dichloromethane (3ml), in the solution of 5-dimethyl-7-hydroxymethyl diamantane (obsolete) (60mg), (1ml is from fuming nitric aicd and Ac2O (2: 3/v: mixture v)) to add cold (0 ℃) 30 ethyl nitric acid.0 ℃ of stirred reaction mixture 15 minutes.(1N, 5ml) solution is used dichloromethane extraction to add two sodium carbonate.Water (10ml * 3) washing extract.Remove in a vacuum and desolvate, by thin layer chromatography, (1: 2, v/v) eluting purification residue obtained oily product (40mg) to use ethyl acetate and hexane. ¹HNMR(DMSO-d ₆，ppm)：7.33(m，5H，C6H5)，7.02(brs，1H，NH)，4.95(s，2H，OCH2)，4.24(s，2H，OCH2)，1.60(s，2H)，1.55(d，2H)，1.44(d，2H)，1.12(m，6H)，0.83(s，6H，2×CH3)。

Embodiment 17:1-amino-3,5-dimethyl-7-

Nitric acid methyl adamantane hydrochlorate (21)

Dissolving 1-(phenyloxycarbonyl) amino-3 in HBr/ acetic acid (1ml), 5-dimethyl-7-nitric acid methyl isophthalic acid-diamantane (obsolete) (17mg) at room temperature stirred 2 hours.Concentrated reaction mixture obtains white solid in a vacuum, obtains purpose product (10mg) with the ether washing. ¹HNMR(DMSO-d ₆，ppm)：7.82(brs，3H)，4.30(s，2H，OCH2)，1.50(s，2H)，1.39(s，4H)，1.19(s，4H)，1.12(a，2H)，0.88(s，6H，2×CH3)。

Embodiment 18:1-acetaldehyde amino-3,5-dimethyl-7-

Synthesizing of nitric acid methyl-diamantane (obsolete) (22)

0 ℃ in nitrogen, in acetic anhydride (0.3ml), add fuming nitric aicd (0.2ml).0 ℃ stir 5 minutes after, add 1 acetaldehyde amino-3,5-dimethyl-7-methylol diamantane (obsolete) (50mg) was 0 ℃ of stirred reaction mixture 1 hour.Reactant mixture is poured in the sodium bicarbonate solution (20ml) of cold (0 ℃), with ether extraction product (10ml).Wash ethereal solution (10ml * 3) with water.Use dried over sodium sulfate solution.Remove in a vacuum and desolvate, and in ether crystallized product, obtain the purpose product. ¹HNMR(DMSO-d ₆，ppm)：7.38(brs，1H，NH)，4.23(s，2H，OCH2)，1.72(a，3H，COCH3)，1.64(s，2H)，1.59-1.56(dd，4H)，1.20-1.06(m，6H)，0.92(s，6H，2×CH3).m.p.154-1550℃.Anal.(C15H24N2O4)，C.H.N.

Embodiment 19: the external neuroprotective of chemical compound 7 unit

Utilization causes 7 pairs of neuronic protections of the inductive damage external model proof chemical compound of NMDA of the gentleness of the neuronic programmed death of brain notochord.At these symptoms (300uM NMDA contact 20 minutes, then wash out), absorb 24 hours by iodate third ingot after, detect the death of neuron program, solid form is permeated neuron (Bonfoco et al., periodical (1995) 92:7162 of institute of NAS) with other technologies.Induce the chemical compound 7 of the NMDA of about 20% neuron program death and 25-100uM obtain from this damage protection (P＜0.001, Fig. 5).

Embodiment 20: the external protection of chemical compound 7 in the mouse brain ischemia model

Utilize 2 hours closure of notochord tremulous pulse (MCA) in the middle of suturing skill carries out in the eye socket, the same approach (Chen, etal., neuroscience (1998) 86:1121) that then is used to stick together ischemia-reperfusion as previously disclosed.But, utilized the C57B1/6 mice of this paper rather than rat.For Memantine hydrochloride, the dosage of loading is 20mg/kg i.p., maintenance dose 1mg/kg 12 hours; show that as the front produced the parenchymal level of 1-10uM in brain, demonstration is neuroprotective (Chen; et al., neuroscience (1998) 86:1121).In order to produce the neuroprotective concentration of chemical compound 7, the dosage of loading is 100mg/kg i.p., and maintenance dose is 40mg/kg i.p., each 12 hours.In each situation, medicine or vehicle Control are at first in the closed administration in back 2 hours of MCA.Chemical compound 7 in this scheme than Memantine hydrochloride neuroprotective (Fig. 6) more.Kill this animal, closed back 48 hours of MCA with TTC staining analysis (Chen, et al., neuroscience (1998) 86:1121).

Embodiment 21: the vasodilation of chemical compound 8 in the rabbit model

With weigh New Zealand's white rabbits of 3-4KG of barbital sodium anesthesia, 13 milligrams of per kilograms.The monkey tremulous pulse that separation descends is removed glutinous company of blood vessel and is organized, and peels off by the Cotton Gossypii point applicator gentleness in the insertion chamber and removes epithelium.Blood vessel is cut into 5 millimeters ring, by the change calculations of record in the isostension connect transmitter tangle (model TO3C, Grass Instruments, Quincy, Mass).At the oxidation Krebs of 20ml suspension, at 37 ℃ of suspension vascular rings, with the inducing sustained contraction of 1uM norepinephrine.Then, in the mode (109 to 10 of dependent dose ^-5M chemical compound 8) lax blood vessel.In some experiments, with methylene blue or the lax pretreatment blood vessel of 30 globulin sealing.

Fig. 7 demonstration utilizes chemical compound 8 arterial vascular lax with contraction in the mode of dependent dose.10 ^-8M can see lax, reaches lax completely at i06M (a).Weaken the lax effect that NO is relevant that shows by serge blue (c) and globulin (d).(b) be the contrast of using solvent.

Fig. 8 has shown site and the specificity that derives from Memantine hydrochloride.That is, chemical compound 9 (a) and 10 (c) neither tell on slight vasoconstriction are arranged simultaneously, and these can be owing to solvent (being presented at the right).Chemical compound 7 (b) has produced the gentleest relaxing in 10uM concentration.

These results prove that chemical compound 7 has vasodilator activity, and the characteristic of NMDA inhibitor and anti-program death is arranged in addition.So chemical compound 7 is by being similar to owing to the mechanism of action effect of the uniqueness of the protection effect of shock in the model.

In all situations, be incorporated herein the scientific publication thing of the various piece of shelves, patent please be incorporated herein by reference in the patent.

Equivalent

From the detailed particular of front of the present invention as seen, should understand that the method for unique treatment neuropsychiatric disorders is narrated.Though this paper discloses specific embodiment in detail, only be for purpose of the present invention is described, it does not limit the scope of attached claim.Particularly, the inventor knows, under the condition that does not break away from the spirit and scope of the present invention that define as claim, can carry out various substituting to the present invention, changes and modification.For example, seriousness or persistent specific nmda receptor antagonist of regulation neuropsychiatric disorders, those skilled in the art's of the knowledge with embodiment as herein described conventional thing is believed in or the selection of specific experiment or mensuration.

List of references

Altamura CA, Mauri MC, Ferrara A, et al. blood plasma and the platelet in neuropsychiatric disorders excites aminoacid, Am J Psyciatry 1993:150:1731-1733.

Ambrozi L and Danielczyk W. treats the brain function of insane damage, Pharmacopsychiat1988 with the Memantine hydrochloride result of II attitude double blind experiment; 21:144-146.

Auer D P, Putz B, Kraft E, et al., glutamic acid reduces in the preceding belt leather layer in depression: part in the body of nuclear magnetic resonance spectroscopy research, Biol.Psychiatry.2000 Feb15:47 (4): 305-13.

Bayerl?JR?and?Gruia?D.Klinsche?Vergleichsstudie?derAntispastika?Memantin?und?Baclofen.{Comparative?Clinical?Studyof?the?Antispastic?Compounds?Memantine?and?Baclofen}.Therapiewozhe?1985；35：5540-5444.

The specificity of Berk M, Plein H, the Belsham B. platelet glutamate receptor hypersensitivity in the psychosis disorder, Life Sci 2000; 66:2427-2432.

Berman RM, Cappiello A, Anand A, but et al. in depressed patient he because of antidepressant effect, Biol Psychiatry.2000; 47:351-4.

Bertolino A, Knable MB, Saunders RC, et al., in schizophrenia, the relation between side back of the body forehead N acetyl aspartic acid mensuration and stricture of vagina dopamine activity.Biol?Psychiatry?1999；45(6)：660-7.

Bhat Mahesh VB, Cha ZW, et al. is worth the location of the N methyl-D-asparagic acid R1 receptor subunits in the special hypophysis prohormone cell type in female rats, and Neuroendocrinology 1995; 62:178-186.

Bormann J. Memantine hydrochloride is the potential repressor of N methyl-D-asparagic acid (NMDA) receptor channel, Eur J Pharmacol 1989; 66:591-592.

Boyer PA, Skolnick P, long term administration imipramine and citalopram have changed the expression of the nmda receptor subunit mRNA in the mouse brain.In the in situ hybridization research quantitatively.J.Mol.Neurosci.1998；10：219-233。

Bremner JD, Innis RB, Salomon RM, et al., positron disperse the relation that tomography is measured cerebral metabolism and the inductive paralepsy of deficiency of tryptophan, Arch.Gen.Psychiat.1997; 54:346-74.

Bremner JD, Narayan M, Anderson ER, et al. Hippocampus volume in adult's depression reduces Am.J.Psychiatry.2000; 157:115-8.Brown ES, Rush AJ, McEwen BS. corticosteroid are to Hippocampus model and damage again: the meaning of emotionally disturbed, and Neuropsychopharmacology 1999; 21:474-84.

Calabrese JR, Bowden CL, Sachs GS, the double blinding placebo Control Study that et al. treats at patient's lamotrigine list with bipolar I depression, Lamictal 602 seminar, J.Clin Psychiatry 1999; 60:79-88.

Carlsson M and Carlsson A.NMDA antagonist MK-801 causes that in the mice that lacks monoamine the locomotor of labelling stimulates J.Neural Transm1989; 75:221-226.

Castillo M, Kwock L, Courvoisie H, et al. in child with the proton MR spectrum of the disorder of bipolar influence: initial observation, AJNR Am J Neuroradiol.2000; 21:832-8.

The proton MR spectrum that Castillo M, Kwock L, Courvoisie H, et al. carry out with bipolar influence disorder in child: initial observation, AJNR Am J Neuroradiol.2000; 21:832-8.

It is depressed that Charney DS, Berman RM, Miller HL. treat, the books in the sick publishing house of Americanism of psychopharmacology.Eds.Alan F.Schatzberg andCharles B.Nemerofff, second edition, company of the sick publishing house of Americanism, 1998,705-732.

Chen DF, Schneider GE, Martinou JC, Tonegawa.BcI-2 promotes the serious axon regeneration among the mammal CNS.Nature?1997；385：434-9.

Chen H-SV, Lipton SA. is the mechanism of the Memantine hydrochloride sealing of the activated passage of NMDA in the cell at rat intestine.J.Physiol(London)1997；499：27-46.

Chen H-SV, Penegrini JW, Aggarwal SK, Lei SZ, Warach S, Jensen FE, the passage of the opening sealing of the NMDA that Lipton SA. Memantine hydrochloride is replied: the neurovirulent treatment advantage of antagonism nmda receptor mediation, J.Neurosci1992; 212:4427-4436.

Chen H-SV; Wang YF; Rayudu PY; Edgecomb P; Neill JC, SegalMM, Lipton SA; the neuroprotective concentration that Jensen FE.NMDA opens passage closure Memantine hydrochloride is not having the Cytoplasm vacuolization after the ischemia administration not have effect, and does not stop labyrinth cognition or LTP.Neuroscience?1998；86：1121-1132.

Choi D. glutamate neurotoxicity and neural disease, Neuron1988; 1:623-634.

The depression of suicide, Cancer Lett.1996 are replied in the variation that Cousins JP and Harper G. shifts the neurobiochemistry in the breast cancer from the Taxol/Neupogen chemotherapy; 110:163-7.

Danysz W, Parsons CG, Kornhuber J, et al. is as the pre-clinical research of the aminoadamantan and the anti-Parkinson compd B of nmda receptor antagonist.Neurosci?Biobehav?Rev?1997；21：455-468.

The effectiveness and the tolerance of the Memantine hydrochloride of Ditzler K. in suffering from the patient of dementia syndrome.Double blinding, placebo control experiment.Arzneim?Forsch/Drug?Res1991；41：773-780.

Prefrontal cortex-tonsil the metabolism of Drevets WC. in adult's depression, AnnNY Acad Sci 1999; 29; 877:614-37.

The neural imaging research of Drevets WC. emotionally disturbed: the meaning of the neural model of adult's depression, Biol Psychiatry 2000; 48:813-829,2000.

Drevets WC, Gautier CH, Price JC, the et al. inductive dopamine of Amphetamine in the people abdomen stricture of vagina relevant with band discharges.Biol?Psychiatry2001；49：81-96

Drevets WC, the abnormality of Price JL, Simpson JR, the et al. knee joint volume cortex in emotionally disturbed.Nature?1997；386(6627)：824-7.

Drevets WC, Price JL, Videen TO, et al. in emotionally disturbed knee joint volume cortex and the metabolic abnormality in the abdomen stricture of vagina, Soc Neurosci Abstr1995; 21 (1): 260.

Duman RS, Malberg J, Nakagawa S, et al. neuronic plasticity and the existence in emotionally disturbed, Biol Psychiatry 2000; 48:732-9.

Ebert D, Feistel H, Barocka A et al. sleep in effective disorder lacks the influence to lower limb system and frontal lobe, with the research of Tc-99m-HMPAO SPECT, Psychiatry Res: neural imaging 1991; 41:247-251.

The influence of Eisenberg E, LaCross S, the Strassman AM. inductive thermal hyperalgesia of clinical experiment nmda receptor antagonist Memantine hydrochloride diagonal angle fork algae in rat, Eur J Pharmacol 1994; 255:123-129.

The behavior of Eisenberg E, Vos BP, Strassman AM. NMDA antagonist Memantine hydrochloride sealing pain in the inductive face ache of formalin, Pain 1993; 54:301-307.

First MB, Spitzer RL, Gibbon M, Williams JBW (1995): the structure clinical observation that DSM-IV Axis I is disorderly, the patient edit (SCID-I/P, Version2.0).Biometrics?Research?Dept.，New?York?State?PsychiatricInstitute.

Fischer PA, Jacobi P, the effect of Schneider E et al.Die Wirkungintravenoser Gaben von Memantin bei Parkinson-Kranken[administration Memantine hydrochloride in Parkinsonian's medium-sized vein].Arzneim-Forsch/DrugRes.1977；27(II)：1487-1489.

Fleischhacker WW, Buchgeher A, the Memantine hydrochloride of Schubert H. in treatment Alzheimer type technetium senile dementia.Prog?Neuro-Psychopharmacol?&?Biol?Psychiat?1986；10：87-93.

Friston KJ, Holmes A, Poline J-B, et al. detects the activation among PET and the fMRI: the level of interference and power, NeuroImage 1996; 40:223-235.

Goldberg JF, Harrow M, Leon AC. are under natural tracking condition, and lithium is treated the disorder of bipolar influence.Psychopharmacol?Bull.1996；32(1)：47-54.

Goodwin FK and Jamison KR. spirit depressing disease, New York: Oxford University Press, 1990.

Gortelmeyer R and Erbler H. Memantine hydrochloride is gentle in medium dementia syndrome in treatment, Arzneim-Forsch/Drug Res 1992; 42:904-913.

Does Greenamyre JT. have the medicine grey matter of glutamic acid antagonist? Ann Neurol1996; 39:557-558.

Greenberg PE, Sistsky T, Kessler RC, et al. be in the financial burden of nineteen ninety anxiety disorder, J.Clin Psychiatry, 1999 Jul; 60:427-35.

Grossman W and Schutz W.Memantin und neurogeneBlasenstorungen im Rhamen spatischer Zustandsbilder.[Memantine hydrochloride and Neurogenic blade functional disorder in the frame work of spastic clinical stitching] .Arzneim-Forsch/Drug Res 1982; 32:1273-1276.

The calculating scale of Hamilton M. depression, J.Neurol Neurosurg Psychiatry.1960; 23:56-62.

Hauang NU, Layer RT, whether Skolnick P.NMDA receptor adapts to the responsible step in the antidepressant effect: In:Skolnick, P.Editor, 1997.Antidepressants:New Pharmacological Strategies Humana, Totowa, NJ, pp.125-144.

Heimer L and Alheid GF (1991): the fascination of the basic volume brain anatomy that combines, In Napier TC, Kalivas PW, Hanin I (eds), The BasalForebrain, New York, Plenum Press, pp.1-42.

Heresco-Levy U and Javitt DC. is in the paathogenic factor of neuropsychopathy syndrome and the effect of the receptor-mediated neurotransmission of N methyl-D-asparagic acid (NMDA) in the treatment, and Eur.Neuropsychopharmacol 1988; 8:141-152.

Hirayasu Y, Shenton ME, Salisbury DF, et al. is belt leather layer volume at one's knees in the paroxysm formula psychosis of beginning, and Am.J.Psychiatry 1999; 156:1091-1093.

Katona C, Abou-Saleh M, Harrison D, et al., lithium strengthen the experiment of the placebo control of fluoxetineand lofepramine, and Br.J.Psychiatry 1995; 166:80-86.

Kim JS, Schmid-Burgk W, Claus D, et al. serum glutaminic acid in depressive patient improves Arch Psychiatrie Nervenkrankheiten 1982; 232:299-304.

Klockgether T and Turski L. excites aminoacid to breathe out ganglion basal: the meaning of treatment Parkinson disease, Trends Neurosci 1989; 12:285-286.

The potential anti-Parkinson effect of antagonist of Klockgether T and Turski L. many targets of L-in the rat that lacks monoamine.Ann?Neurol?1990；28：539-546.

Kornhuber J, Bormann J.Hubers M, et al. are in the influence of the 1-amine-diamantane (obsolete) of the MK-801 of nmda receptor gated ion channels binding site: the people is the research of brain after death, Eur J Pharmacol (Mod Pharmacol Sect) 1991; 206:297-300.

Kornhuber J, Bormann J, Retz W, et al. replace [H3] MK-801 combination with the bonded Memantine hydrochloride of treatment concentration in people's volume cortex after death.Eur?JPharmacol，1989；166：589-590.

The diamantane (obsolete) that Kornhuber J, Weller M, Scchoppmeyer K, et al. have Memantine hydrochloride is the nmda receptor antagonist with neuroprotective properties.J.NeurolTransm?Suppl；1994；43：91-104.

The brain notochord liquid of Kornhuber J and Quack G. philtrum is breathed out the serum-concentration of N methyl-D-asparagic acid (NMDA) receptor antagonist Memantine hydrochloride.NeurosciLetters?1995；195：137-139.

Laurenza A, Asnis G, Beaman M, Hudson J, Khan A, LondborgP, Monaghan E, Rudd D. is supported in the one pole depression, the double blinding of the influence of the Lamotrigine in the bipolar disorder (Lamictal ), the research 1999 of placebo control; 1 (S1): 39-40.

The protection of Leon AC. placebo is from non-main body of replying, the paradox of powder, ArchGen Psychiatry 2000; 57:329-330.

The Memantine hydrochloride multicenter study is used in the motion disorder that Leskow P.Trerapie zentral bedingter Bewegungsstorungen:Multicenterstudie mit memantine.{ therapeutic community determines }.Trherapiewoche?1987；37：4843-4845.

Levine J, Panchalingam K, Rapoport A, the brain notochord liquid glutamic acid level of the raising of et al. in depressive patient, 2000; 47:586-593.

The prospect of Lipton SA. clinical tolerance NMDA antagonist: the nitric oxide production passage closure of opening breathe out or redox state, Trends Neurosci1993; 16:527-532.

Maes M, Verkerk R, Vandoolacghe E, et al. excites aminoacid, serine in the treatment antidepressant, glycine, histidine, threonine, taurine, alanine is breathed out arginic serum levels: breathe out the prediction of clinical response, Acta Psychiatr Scand.1998 Apr with the adjusting of antidepressant treatment; 97 (4): 302-8.

The influence of Maj J. Memantine hydrochloride centering nervus cardiacus transmission system CA, result's summary, Arzneim Forsch/Drug Res 1982; 32:1236-1273.

Manji HK, do Moore GJ, Chen G. have the observed cationic neuroprotective effect of this uniqueness at 50 lithium? Biol Psychiatry 1999; 46 (7): 929-40.

Manji HK, Moore GJ, Chen G. be lithium rise cytoprotective PROTEIN B cl-2 in CNS in vivo: the effect of parent's nerve and neuroprotective effect in manic-depressive illness, and J.Clin.Psychiatry 2000; 61:Suppl 9:82-96.

Mathis P, Schmitt L, Benatia M, et al. blood plasma aminoacid is upset and is breathed out depression, and Encephale 1988; 14:77-82.

Mauri MC, Ferrara A, Boscati L, et al. blood plasma in the depressed patient who breathes out under the Fluvoxamine treatment of reduction adult is breathed out the placebo amino acid concentration, and Neuropsychobiology 1998; 37 (3): 124-9.

McEwen BS and Sapolsky RM. coerces and breathes out cognitive function, Curr OpinNeurobiol.1995 Apr; 5 (2): 205-16.

The effect of N-methyl-D-aspartate (NMDA) receptor among the experiment catalepsy of Mehta AK and Ticku. in rat.Life?Sci?1990；46：37-42.

Meltzer CC, Kinahan PE, Greer PJ, the partial volume based on MR of et al.PET concerns the comparative assessment of scheme, J Nucl Med 1999; 40:2053-2065.

Miltner FO. treats the value of symptom, the synergistic development of the stretching, extension in the stupor with big brain stem symptom with Memantine hydrochloride in big coma I.Arneimittelforschung.1982；32(10)：1271-3.

Montgomery SA and Asberg M. design is to changing responsive new depressed scale, Br J Psychiatry 1979; 134:382-389.

Moore GJ, Bebchuk JM, Hasanat K, et al. are in human brain, and lithium improves N acetyl aspartic acid: evidence in the body in the close neural effect of supporting bcl-2 ', BiolPsychiatry 2000a/48:1-8.

Moore GJ, Bebchuk JM, Wilds IB, et al. lithium in people's ectocinerea is induced increase, Lancet 2000b; 356:1241-2.

Mundinger F and Milios E.[moves disorderly in conjunction with the experience of using Memantine hydrochloride in the surgery of three-dimensional location outside treating serious spasm and cone.Nervenarzt.1985?Feb；56(2)：106-9.

Murray CJ and Lopez AD. whole world fatality rate, Disability is breathed out the distribution of risk factor: the burden of the disease research in the whole world, Lancet 1997; 349:1436-42.

Musselman DL, Evans DL, the relation of Nemeroff CB. depression and cardiovascular disease: epidemiology, biology and treatment, Arch Gen Psychiatry.1998; 55:580-92.

Nakamura S. antidepressant is induced the regeneration of the catecholaminergic state terminal in the rat notochord cortex.NeurosciLett?1990；111：64-8.

Nibuya M, Morinobu S, the adjusting that the BDNF and the trkB mRNA of anti depressant medication are breathed out in the chronic electrofit tic of Duman RS., J.Neurosci, 1995Nov; 15 (11): 7359-47.

Nibuya M, Nestler EJ, Duman RS, the antidepressant administration improves the expression that cAMP replys element conjugated protein (CREB), J Neurosci.1996Apr 1 in rat hippocampus; 16 (7): 2365-72.

Nierenberg AA: the methodology problem in the depressed research of treatment resistance, Psychopharmacol Bull.1994; 190; 26:461-464.

Nijolajsen L, Gotrrup H, Kristensen AGD, et al, cut off or surgery after Memantine hydrochloride (N-methyl-D-aspartate receptor antagonist) in treatment europathology pain: arbitrarily, double blinding, crossing research, Anesth Analg2000; 91:960-966.

Nikolajsen L, Hansen CL, Nielsen J, but et al. it because of influence to phanthom pain: the disorder of periphery input centering nervus cardiacus pathology keep Pain1996; 67:69-77.

Nowak G, Ordway GA, Paul IA. be the change of N-methyl-D-aspartate (NMDA) receptor complex in the volume cortex in suicide, Brain Res 1995; 675:157-164.

Nowak G, Trullas R, Layer RT, et al. is at the adaptations with the N-methyl-D-aspartate receptor complex behind the chronic treatment of imipramine and 1-amino-cyclopropane aneca carboxylic acid, J.Pharmacol Exp Ther 1993; 265:1380-1386.

Neuroglial minimizing in Ongur D, Drevets WC, the Price JL. cortex of volume at one's knees in emotionally disturbed, Pro Natl Acad Sci USA 1998; 95:13290-13295.

Ossowska K, Pietraszek M, Wardas J, et al. is at the antipsychotic drug effect of glutamate receptor on, Amino Acids 2000; 19 (1): 87-94.

Pantev M, Ritter R, Gortelmeyer R. suffer from slightly clinical assessment of breathing out behavior in the long-term care patient of medium dementia, Zeitschriftfur Gerontopsychologie und Psychiatrie 1993 under Memantine hydrochloride treatment; 6:103-117.

Parker G and Hadzi-Pavlovic D (Eds) (1996): Melancholia: the disorder of emotion, New York: Cambridge University Press are breathed out in motion.

Paul IA, Nowak G, Layer RT, the adaptability of et al. N-methyl-D-aspartate receptor behind chronic anti depressant therapy, J.Pharmacol ExpTher1994; 269:95-102.

It is disorderly that Paul IA.NMDA receptor is breathed out influence, at SkoInick, and P.Editor.Antidepressants:New Pharmacological Strategies Humana, Totowa, NJ, 1997, pp.145-158.

Puigdemont D, Perez V, the depressed follow up study of the anti-adult of Perez-Blanco J et al.: the summary of psychotic X world convention; August 23-28,1996; Madrid, Spain; 1996; 2:336-337.

Rabey JM, Nissipeanu P, the effectiveness of the nmda receptor antagonist in the dark disease of Korczyn AD. Memantine hydrochloride treatment handkerchief gold, J Neural Transm 1992; 4:277-282.

After death the studies show that neuron of Rajkowska G. in emotionally disturbed breathed out the variation that glial cell has number, Biol Psychiatry 2000; 48:766-77.

Rajkowska G, Miguel-Hidalgo JJ, Wei J, the neuron of et al. in adult's depression breathed out the form evidence in the colloid volume page or leaf cell pathology, Biol Psychiatry 1999; 45:1085-98.

The result of the clinical experiment of the changeable in mood compound Memantine hydrochloride of Rohde H.[psychosis] .Fortschr Me.1982 Nov 18; 100 (43): 2023-6.

Rosenberg DR, MacMaster FP, Keshavan MS, et al. forces the decline of tail glutamic acid energy concentration among the disorderly patient, J Am Acad Child Adolesc Psychiatry.2000Sep with the department of pediatrics obesity of paroxetine treatment; 39 (9): 1096-103.

Rusinek H and Chandra R. is from the cerebral tissue cubing of magnetic resonance imaging, Invest Radiol 1993; 28:890-895.

The neurovirulent probability of Sapolsky RM. Hippocampus in adult's depression: the prelude of neuronal death, Biol Psychiatry 2000; 48 (8): 755-65

Schmidt WJ, Bubser M, Hauber W. excites aminoacid to breathe out parkinson disease, Trends Neurosci 1990; 13:46-47.

Schneider E, Fischer PA, Clemens R, the oral menantine administration of et al.Wirkungen oralerMemantin-Gaben auf die Parkinson-Symptomatik.{ is to the influence of parkinson symptom: the result of the multicenter study of placebo control }.Dtsch?Med?Wschr?1984；109：987-990.

Schulz R, Beach SR, Ives DG, Martire LM, Ariyo AA, Kop WJ. depression in being grown up old age is breathed out lethal combination: cardiovascular health research, Arch InternMed, 2000 Jun 26; 160 (12): 1761-8.

Sheline YI, Sanghavi M, Mintun MA, et al. in the medical science healthy women of suffering from present adult's depression depressed lastingly but be not age prediction Hippocampus volume lose J Neurosci 1999; 5034-43.

Sheline YI, Wang PW, the atrophy of Gado MH et al. Hippocampus in present adult's depression, Proc Natl Acad Sci USA 1996; 93:3908-13.

The antidepressant of the millenium that Skolnick P. is new, Eur.J.Pharmacol.1999 Jun 30; 375 (1-3): 31-40.

Thase ME and Rush AJ. treatment resistance depression, In:Bloom FE, KupferDJ, eds, Psychopharmacology:The fourth Generation of Progress.New York, NY:Raven Press; 1995:1081-1098.

Tohen M, Hennen J, Zarate CM Jr, Baldessarini RJ, StrakowskiSM, Stoll AL, Faedda GL, Suppes T, Gebre-Medhin P, Cohen BM. in 219 cases of the insane disorder of the adult influence of outbreak first, the syndrome in 2 years breathe out functional restoration, Am J Psychiatry.2000 Feb; 157 (2): 220-8.

The N acetyl aspartic acid of Tsai G and Coyle JT. in neuropsychiatric disorders, Prog Neurobiol 1995; 46:531-40.

Walder DJ, Walker EF, the cognitive function of Lewine RJ. in suffering from schizoid patient, notochord discharges, and breathes out serious symptom.Biol?Psychiatry2000；48：1121-1132.

Weseman W, the metabolism disorder of Sturm G, Funfgeld EW. potential anti-Parkinson medicine Memantine hydrochloride in the people.J.Neural?Transm?Supol?1980；143-148.

West J, Fitzpatrick J, Wang MY et al. review examine intermodality brain imaging register technique relatively breathe out the assessment, J.Comp.Assist Tomogr 1997; 21 (4): 554-66.

Winsberg?ME，Schs?N，Tate?DL，et?al。Volume N-acetyl aspartic acid outside the back of the body of the minimizing in bipolar disorder, Biol Psychiatry, 2000; 47:475-81.

Wong JCH, Studholme C, Hawkes DJ, the restriction of the visible detection of the imaging error logging of et al. in the fluorescence-18-fluorodeoxyglucose PET-MRI research of brain.Eur?J?Nucl?Med?1997；24(6)；642-50.

Woods RP, Masotho J, Cherry SR (1993): with the MRI-PET registration of automatic algorithms, J.Comput Assist Tomogr 17:536-546.

The influence that Wu JC, Gillin JC, Buchsbaum MS, et al. sleep in the brain metabolism of depressive patient and lack, Am J Psychiatry 1992; 149:538-543.

The economic evaluation of Wyatt RJ and Henter I. manic-depressive illness, 1991, SocPsychiatr Psychiatr Epidemiol 1995; 30:213-9.

Young RC, Biggs JR, Ziegler VE, the calculating scale of et al. mania: dependency, effectiveness is breathed out sensitivity, Br J Psychiatry 1978; 133:429-435.

Claims

1. method for the treatment of neuropsychiatric disorders, comprise nmda receptor antagonist chemical compound to people patient's effective dosage of suffering from neuropsychiatric disorders, be adjusted in the glutamic acid energy neurotransmission of the nmda receptor among the people patient, thus the treatment neuropsychiatric disorders.

2. according to the process of claim 1 wherein that neuropsychiatric disorders is that the adult is depressed.

3. according to the process of claim 1 wherein that neuropsychiatric disorders is bipolar disorder.

4. according to the process of claim 1 wherein that neuropsychiatric disorders is an anxiety.

5. comprise that according to the process of claim 1 wherein that neuropsychopathy is selected from medicine is crazy about, drug dependence, medicine is shunk back and is breathed out drug resistance.

6. according to the process of claim 1 wherein that excessive glutamic acid can regulate by neurotransmission, thereby adjusting glutamic acid is to the neuronic toxic effect that excites.

7. according to the method for claim 6, wherein regulate glutamic acid and provide the neuroprotective effect the neuronic toxic effect that excites.

According to the process of claim 1 wherein nmda receptor antagonist chemical compound regulate the bone propylhomoserin can notochord cortex stricture of vagina or the subthallamicopalladial approach in the nmda receptor activity.

9. method according to Claim 8, wherein nmda receptor antagonist chemical compound regulate rely on glutamic acid that dopamine or norepinephrine discharge can the notochord stricture of vagina or the subthallamicopalladial approach in activity.

10. according to the process of claim 1 wherein that nmda receptor antagonist chemical compound comprises Memantine hydrochloride, the nitro Memantine hydrochloride, its enantiomer or its drug acceptable salt, chemical compound is 0.1mg/day-100mg/day to the dosage range of people patient's administration.

11. according to the method for claim 10, wherein nmda receptor antagonist chemical compound is 5mg/day-80mg/day to the dosage range of people patient's administration.

12. according to the method for claim 10, wherein nmda receptor antagonist chemical compound is 10mg/day-35mg/day to the dosage range of people patient's administration.

13., wherein provide the patient treatment of suffering from neuropsychiatric disorders effect according to the method for claim 10.

14. method of utilizing glutamic acid energy neurotransmission among the nmda receptor antagonist chemical compound mediator patient, comprise nmda receptor antagonist chemical compound to patient's effective dosage of suffering from neuropsychiatric disorders, nmda receptor among the antagonism people patient, thereby regulate glutamic acid energy neurotransmission, thereby treatment neuropsychopathy with nmda receptor.

15. according to the method for claim 14, wherein neuropsychiatric disorders is that the adult is depressed.

16. according to the method for claim 14, wherein neuropsychiatric disorders is bipolar disorder.

17. according to the method for claim 14, wherein neuropsychiatric disorders is an anxiety.

18. according to the method for claim 14, wherein neuropsychiatric disorders is selected from and comprises the medicine addiction, drug dependence, and medicine is shunk back and is breathed out the group of drug resistance.

19. according to the method for claim 14, wherein the antagonism nmda receptor is regulated glutamic acid to the neuronic toxic effect that excites in people patient.

20., wherein regulate glutamic acid and provide the neuroprotective effect to the neuronic toxic effect that excites according to the method for claim 19.

21. according to the method for claim 14, wherein the nmda receptor in nmda receptor antagonist chemical compound adjusting glutamic acid energy notochord stricture of vagina or the subthallamicopalladial approach is active.

22. according to the method for claim 21, wherein nmda receptor antagonist chemical compound approach relies on the glutamic acid energy notochord stricture of vagina of dopamine or norepinephrine release or the activity in the subthallamicopalladial approach.

23. according to the method for claim 14, wherein nmda receptor antagonist chemical compound comprises Memantine hydrochloride, the nitro Memantine hydrochloride, and its enantiomer, or its drug acceptable salt, and this chemical compound is 0.1mg/ days-100mg/ days to the dosage range of people patient's administration.

24. according to the method for claim 14, wherein nmda receptor antagonist chemical compound is that 5 mg/day are to 80 mg/day to the dosage range of people patient's administration.

25. according to the method for claim 14, wherein nmda receptor antagonist chemical compound is that 10 mg/day are to 35 mg/day to the dosage range of people patient's administration.

26. according to the method for claim 14, wherein the antagonism nmda receptor provides suffering from people's patient treatment effect of neuropsychiatric disorders in people patient.

27. method of in people patient, utilizing nmda receptor antagonist chemical compound to regulate glutamic acid energy neurotransmission; comprise nmda receptor antagonist chemical compound to patient's effective dosage of suffering from neuropsychiatric disorders; the NK-801 binding site of PCP among the antagonism people patient or nmda receptor; thereby regulate excessive glutamic acid energy neurotransmission by nmda receptor; thereby provide people patient's neuroprotective effect to breathe out close neural effect, thereby treatment neuropsychiatric disorders.

28. according to the method for claim 27, wherein nmda receptor antagonist chemical compound comprises menantine, the nitro Memantine hydrochloride, and its enantiomer, or its drug acceptable salt, chemical compound is 0.1mg/day-100mg/day to the dosage range of people patient's administration.

29. according to the method for claim 27, wherein nmda receptor antagonist chemical compound is that 5 mg/day are to 80 mg/day to the dosage range of people's administration.

30. according to the method for claim 27, wherein nmda receptor antagonist chemical compound is that 10 mg/day are to 35 mg/day to the dosage range of people patient's administration.

31. according to the method for claim 27, wherein neuropsychiatric disorders is selected from and comprises that the adult is depressed disorderly, bipolar disorder, and anxiety, the medicine addiction, drug dependence, medicine are shunk back and the group of Drug tolerance.

32.NMDA the application of receptor antagonist compounds in making the medicine that utilizes the excessive glutamic acid energy neurotransmission of regulating nmda receptor to be used for the treatment of the people patient who suffers from neuropsychiatric disorders.

33. according to the nmda receptor antagonist application of compound of claim 32, it is PCP or the MK-801 binding site that is used for antagonism people patient nmda receptor.

34. according to the nmda receptor antagonist application of compound of claim 33, it is the excessive glutamic acid energy neurotransmission that is used to regulate nmda receptor, thereby provides people patient's neuroprotective effect to breathe out close neural effect, thereby treatment neuropsychiatric disorders.

35. according to the nmda receptor antagonist application of compound of claim 32, wherein the dosage range of people patient's nmda receptor antagonist chemical compound is provided is 0.1mg/ days-100mg/ days to medicament.

36. according to the nmda receptor antagonist application of compound of claim 32, wherein the dosage range of people patient's nmda receptor antagonist chemical compound is provided is 5mg/day-80mg/day to medicament.

37. according to the nmda receptor antagonist application of compound of claim 32, wherein the dosage range of people patient's nmda receptor antagonist chemical compound is provided is 10mg/ days-35mg/ days to medicament.