WO2007141600A1 - Current dependent nmda antagonists - Google Patents
Current dependent nmda antagonists Download PDFInfo
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- WO2007141600A1 WO2007141600A1 PCT/IB2006/051783 IB2006051783W WO2007141600A1 WO 2007141600 A1 WO2007141600 A1 WO 2007141600A1 IB 2006051783 W IB2006051783 W IB 2006051783W WO 2007141600 A1 WO2007141600 A1 WO 2007141600A1
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- nmda
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- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 title claims abstract description 104
- 230000001419 dependent effect Effects 0.000 title claims abstract description 96
- 239000005557 antagonist Substances 0.000 title claims abstract description 94
- 239000003814 drug Substances 0.000 claims abstract description 14
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- 229930195712 glutamate Natural products 0.000 claims description 39
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- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 description 3
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- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 description 1
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- BFNCJMURTMZBTE-UHFFFAOYSA-N aptiganel Chemical compound CCC1=CC=CC(N(C)C(N)=NC=2C3=CC=CC=C3C=CC=2)=C1 BFNCJMURTMZBTE-UHFFFAOYSA-N 0.000 description 1
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- DKFAAPPUYWQKKF-GOEBONIOSA-N gacyclidine Chemical compound C[C@H]1CCCC[C@@]1(C=1SC=CC=1)N1CCCCC1 DKFAAPPUYWQKKF-GOEBONIOSA-N 0.000 description 1
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- WHUUTDBJXJRKMK-VKHMYHEASA-L glutamate group Chemical group N[C@@H](CCC(=O)[O-])C(=O)[O-] WHUUTDBJXJRKMK-VKHMYHEASA-L 0.000 description 1
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Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/94—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors
- G01N33/9406—Neurotransmitters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6872—Intracellular protein regulatory factors and their receptors, e.g. including ion channels
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2500/00—Screening for compounds of potential therapeutic value
Definitions
- NMDA antagonist refers to non-competitive channel blocking NMDA antagonists.
- the competitive NMDA antagonist which competes with glutamate for its binding site at the NMDA receptor, is an other type of NMDA antagonist, which however is not relevant for this disclosure.
- the non-competitive open channel blocking NMDA antagonists to which this invention refers have a binding site inside the NMDA receptor ion channel. It is thought that they can access this binding site only when the channel is opened. Therefore, they are described as use dependent NMDA antagonists. Unless the channel is used and opened, they cannot access the binding site.
- the affinity of the N-ethyl compound for the binding site is 5.7 times lower than that of the N-methyl analog, 4.1 times lower than that of the primary amine, and 18.9 times lower than that of (+)-MK-801.
- the glutamate stimulated Ca + influx test it is the second most potent compound, surpassed only slightly by (+)-MK-801. It also has high potency in the NMDA lethality test.
- it has much lower affinity for the binding site it has equal biological activity with compounds with much higher affinity for the binding site. Therefore, the biological activity is independent from the affinity for the binding site. This finding is counter-intuitive and surprising. The Applicant has therefore sought an explanation for this surprising finding, which the authors of the original study ignored.
- these 4a-hexahydrofluorenamines bind to the binding site on the inside wall of the NMDA receptor ion channel in such a way that the substituent on the nitrogen extends out into the open channel and blocks it for Ca 2+ ions.
- the N-ethyl substituent is too large for the normally opened channel, this compounds can not enter the channel efficiently, therefore there is a sharp drop in displacement of [3H]TCP.
- the width of the channel is so large that it can also accommodate the larger N-ethyl substituent. This compound then enters the channel easily and binds to the binding site with high affinity. Therefore, it has high activity in the biological tests.
- the hydrogen and methyl substituted amines do not block the open space of the widely opened channel as efficiently as the ethyl substituted compound when it is opened very widely, they are less efficient in inhibiting glutamate stimulated Ca influx.
- closed channel binding NMDA antagonists were selected. Closed channel binding NMDA antagonists are not use or current dependent and will necessarily be unsuitable as therapeutic agents.
- the diameter of the opening of the channel is dependent on the NMDA agonist concentration and determines the current that flows through the channel. For a higher current to flow, the channel must be opened wider. Therefore, those NMDA antagonists which can access the channel and bind to the binding site inside the channel only above a certain width of opening, or above a certain current flowing through the NMDA receptor ion channel, but not below a certain width of opening, or below a certain current flowing through the NMDA receptor ion channel, can be described as current dependent NMDA antagonists. Their affinity for the binding site remains essentially the same, but they do not gain access to the binding site, so their affinity appears lower when they are tested under low glutamate conditions, or in the absence of glutamate. The ability of a current dependent NMDA antagonist to access the binding site is dependent on the opening width of the ion channel, or the current flowing through the ion channel, and such a current dependent NMDA antagonist will therefore block higher currents more than lower currents.
- such current dependent NMDA antagonists may be able to bind to the binding site in two different conformations: one conformation with low affinity for the binding site in which a flexible substituent extends along the ion channel opening, and one conformation with high affinity for the binding site where this substituent extends out into the opening of the ion channel.
- the molecule will then adopt the configuration which the width of the channel permits. If the width of the opening of the ion channel is large enough for the molecule to adopt the high affinity configuration, it will bind with high affinity to the binding site and efficiently block the current through the ion channel. Else it will bind in the low affinity conformation and have less blocking effect on the current. Therefore, dependent on the opening width of the ion channel, or the current flowing through the ion channel, a current dependent NMDA antagonist may bind to the binding site in a low and a high affinity conformation and block higher currents more than lower currents.
- Such current dependent NMDA antagonists will block the NMDA receptor ion channel more above a certain current threshold, and much less below a certain current threshold. This has the advantage that only high currents of pathologically active NMDA receptors are blocked very efficiently due to the high affinity for the binding site, while currents of normally active NMDA receptors remain unaffected, because the NMDA antagonist can't access its binding site or has low affinity for the binding site.
- An additional advantage is that current dependent NMDA antagonists will block the wide open channel more completely due to their size, which fills the wide open channel, while previously known NMDA antagonists optimized for high affinity under normal conditions, or even for closed channel affinity, are too small to completely block the wide open channel.
- NMDA antagonists do not show such current dependency in the blocking effect on the NMDA receptor. They block normally, physiologically active NMDA receptors as efficiently as, or actually more efficiently than, pathologically over-active NMDA receptors and therefore cause a variety of side effects which make them unsuitable for clinical application.
- Memantine is a noteworthy exception since it also shows current dependency, but what causes its current dependency seems unclear, and it also does not bind to the PCP binding site. Its mechanism of current dependency is likely different from that of the disclosed current dependent NMDA antagonists.
- a disadvantage of memantine is that it does not efficiently block over-active NMDA receptors, but only gradually reduces the current.
- NMDA antagonists for highest affinity for the binding site under physiological conditions, or even for closed channel binding site affinity, inevitably selected for the compounds with the worst therapeutic properties, because NMDA antagonists selected by this method will block all normally active NMDA receptors and therefore lead to severe side effects. Moreover, they do not efficiently block NMDA receptors under high, pathological glutamate concentrations, and therefore are not effective therapeutic agents. Current dependent NMDA antagonists, due to their selectivity for pathologically active NMDA receptors, have good chances of succeeding where previously tested NMDA antagonists have failed. Since such current dependent NMDA antagonists will efficiently block over-currents through NMDA receptors, but not normal currents, they may also constitute novel and valuable therapeutic agents for the treatment of epilepsy.
- a first method to identify current dependent NMDA antagonists consists in measuring the affinity of a compound for the PCP binding site of the NMDA receptor at different concentrations of a NMDA agonist. Those compounds which show a lower affinity for the binding site when the NMDA agonist concentration is lower, and a higher affinity for the binding site when the NMDA agonist concentration is higher, are current dependent NMDA antagonists.
- the NMDA agonist used is glutamate
- the lower concentration of the NMDA agonist glutamate is the concentration found under normal, physiological conditions
- the higher concentration of the NMDA agonist glutamate used is the concentration found under pathological conditions, under which the NMDA receptor needs to be blocked.
- a second method to identify current dependent NMDA antagonists consists in measuring the effect of a compound on the NMDA agonist induced current through the NMDA receptor ion channel. Those NMDA antagonists which are reducing or blocking currents more above a certain threshold, or above a certain concentration of the NMDA agonist, and less below a certain threshold, or below a certain concentration of the NMDA agonist, are current dependent NMDA antagonists.
- the NMDA agonist used to induce the NMDA receptor current is glutamate, and the lower concentration of the NMDA agonist glutamate is the concentration found under normal, physiological conditions, while the higher concentration of the NMDA agonist glutamate used is the concentration found under pathological conditions, under which the NMDA receptor needs to be blocked.
- This is the best and most conclusive method to identify and characterize current dependent NMDA antagonists. It will also reliably identify current dependent NMDA antagonists which do not bind to the PCP binding site. This method furthermore allows to determine the exact characteristics of a current dependent NMDA antagonist by making multiple measurements at multiple concentrations of the NMDA agonist.
- a third method to identify current dependent NMDA antagonists consists in measuring the NMDA agonist dependent Ca 2+ influx into cells bearing a NMDA receptor at different concentrations of a NMDA agonist. Those NMDA antagonists which are reducing or blocking the NMDA agonist dependent Ca 2+ influx into cells more at a higher concentration of the NMDA agonist, and less at a lower concentration of the NMDA agonist, are current dependent NMDA antagonists.
- the NMDA agonist used to induce the NMDA agonist dependent Ca influx into cells is glutamate, and the lower concentration of the NMDA agonist glutamate is the concentration found under normal, physiological conditions, while the higher concentration of the NMDA agonist glutamate used is the concentration found under pathological conditions, under which the NMDA receptor needs to be blocked.
- a fourth method to identify current dependent NMDA antagonists consists in measuring the 5-HT2A agonist facilitated NMDA receptor current in the presence of a test compound.
- the facilitation of NMDA currents by 5-HT2A agonists has been disclosed by Arvanov et al. in Eur J Neurosci. 1999 Aug;l l(8):2917-34, 1999 (PMID: 10457188) and Eur J Neurosci. ll(9):3064-72, 1999 (PMID: 10510170).
- 5-HT2A agonist facilitated NMDA currents can be found in Lambe EK, Aghajanian GK, Hallucinogen-Induced UP States in the Brain Slice of Rat Prefrontal Cortex: Role of Glutamate Spillover and NR2B-NMDA Receptors. Neuropsy- chopharmacology. 2005 Nov 2; [Epub head of print] (PMID: 16292328).
- the normal and the 5-HT2A agonist facilitated NMDA receptor currents are recorded according to the methods described in these publications in the presence and absence of a NMDA antagonist.
- a fifth method to identify current dependent NMDA antagonists consists in measuring the neuroprotective activity of a compound against the neurotoxicity of high concentrations of a NMDA agonist. Those compounds which have relatively low affinity for the PCP binding site, but comparatively high activity against the toxicity of the NMDA agonist are current dependent NMDA antagonists. Those compounds which have very high neuroprotective potency, but only very modest binding affinity for NMDA receptors when measured under low glutamate concentrations of in the absence of glutamate, are the most suitable drug candidates. Since mechanisms other than NMDA antagonism can cause neuroprotection, it needs to be verified with other methods that compounds identified with this method actually act as current dependent NMDA antagonists.
- (+)-N-methyl-10,5-(iminomethano)-10,l l-dihydro-5H-dibenzo[ ⁇ , J]cycloheptene is a current dependent NMDA antagonist.
- (+)-N-methyl-IDDC has a 22-fold lower affinity for the binding site than (+)-K)DC, (+)-10,5-(iminomethano)-10,ll-dihydro-5H- dibenzo[ ⁇ ,J]cycloheptene, but it is almost as effective as a neuroprotective agent.
- the first method described may be used, for example, for the initial screening of a large number of different compounds, because it can be performed quickly and cheaply and gives a good first indication of the current dependency of a NMDA antagonist.
- Those compounds which give an indication of current dependency using this method may then be further investigated using the second method to fully characterize the current dependent NMDA antagonistic properties of the compound.
- NMDA antagonists available for testing by the disclosed methods.
- the Applicant has therefore devised a method to design current dependent NMDA antagonists.
- Any known NMDA antagonist binding to the PCP binding site of the NMDA receptor with reasonably high affinity may be modified to become a current dependent NMDA antagonist by increasing the size of the molecule to such a size that it can not access the inside of the closed or normally opened NMDA receptor ion channel any more, but can still access it when it is excessively opened.
- the size of the molecule is gradually increased in such a position where the additional bulk does not interfere with the binding to the binding site, but extends into the open channel. The further this additional bulk extends out into the open channel, the higher is the threshold current where the switch from apparent low affinity to apparent high affinity occurs.
- N- substituent should be a rigid cycloalkyl rather than a flexible alkyl group, to ascertain that it extends into the channel and does not align along the channel. Such alignment will happen if the N-substituent is too large to extend into the channel and will cause a drop in affinity for the binding site.
- NMDA antagonists only have reduced affinity, their affinity is however not current dependent.
- N-Butyl-1-phenylcyclo- hexylamine for example has both lower affinity for the PCP site and lower biological activity than PCP.
- R ethyl, isopropyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, (R)- and (S)-2-butyl, (R)- and (S)-2-but-3-ene, (R)- and (S)-2-but-3-yne.
- R aryl, preferably phenyl, 2-thienyl, 2-toluyl, 2-chlorophenyl, 3-hydroxyphenyl,
- R 3 H, NH 2 , OH
- (+)-N-methyl-IDDC shows very interesting properties indicating that it is a current dependent NMDA antagonist. It is also a highly rigid molecule where every substituent is held in a precisely defined position. Furthermore, the compound with the highest affinity for the binding site in this series, 3-fluoro-(+)-IDDC, has excellent affinity, with an IC 50 of 15.5 nM against [3H]
- glutamate concentrations up to about 3 ⁇ M are normal, physiological glutamate concentrations, while glutamate concentrations above 3 ⁇ M are toxic, pathological glutamate concentrations. This is useful information when identifying current dependent NMDA antagonists according to the methods disclosed.
- the threshold glutamate concentration where the current dependent NMDA antagonist gains access to the binding site should therefore be around 3 ⁇ M.
- (+)-N-methyl-IDDC has its threshold around this desirable level.
- (+)-IDDC is actually neurotoxic under low glutamate concentrations. At 3 ⁇ M glutamate, the cell survival is reduced in the presence of (+)-IDDC, but not in the absence of (+)-IDDC. N-Methyl-IDDC does not show such a neurotoxic effect. This can now be explained, because N- methyl-IDDC is a current dependent NMDA antagonist which does not block normally active NMDA receptors below a glutamate concentration of about 3 ⁇ M.
- (+)-N-methyl IDDC ( 10 ⁇ M) inhibited the NMDA current in a use-dependent and voltage-dependent manner. Serial applications evoked progressively smaller currents. Inhibition by (+)-N-methyl IDDC was reversed only with prolonged or repeated application of NMDA. The rate of recovery from blockade by (+)-N-methyl IDDC was somewhat more rapid than the rate of recovery of responses following MK-801. This observation is consistent with the observation that (+) N- methyl IDDC has a lower affinity than MK-801 for the PCP receptor.”
- (+)-N-methyl-IDDC and its derivatives have highly desirable properties as current dependent NMDA antagonists.
- a rapid recovery from the blockage of NMDA receptors is an important factor to enable fast recovery from blockage when normal glutamate concentrations are restored. Rapid recovery from blockage enables the restorage of normal synaptic transmission, which is essential for neuronal survival.
- IDDC derivatives of IDDC as anticonvulsants and muscle relaxants. It is well known that NMDA antagonists have anticonvulsant and muscle relaxant effects. While N- and 10-substituted derivatives of IDDC are claimed as anticonvulsants and muscle relaxants, IDDC itself is specifically excluded in GB 1146109. Apparently, the authors have found IDDC unsuitable as drug, and this can now be explained easily: IDDC is not a current dependent NMDA antagonist and therefore unsuitable for therapeutic applications. As can be seen from the data disclosed in these patents, this series of compounds also has very good oral bioavailability, which is very advantageous.
- (+)-IDDC the 10-position of (+)-IDDC is an additional attractive site for adding bulk to the parent molecule.
- Molecular modeling studies also show that the substituents on the nitrogen and the 10-position extend in the same direction, apparently into the open channel.
- a fluorine in the 3-position of (+)-IDDC has been shown to increase affinity, and it will likely have a positive effect on the metabolic stability of the drug.
- 3,7-Difluoro-(+)-IDDC has only slightly reduced affinity (racemate 51.2 nM, estimated for (+)-enantiomer 26 nM compared to 15.5 nM for 3-fluoro-(+)-IDDC), but can be expected to have even better metabolic stability.
- R H, methyl, ethyl, isopropyl, allyl, propargyl, cyclopropyl, cyclobutyl, cy- clopentyl, cyclohexyl, adamantyl, (R)- and (S)-2-butyl, (R)- and (S)-2-but-3-ene, (R)- and (S)-2-but-3-yne
- R H, methyl, ethyl, isopropyl, cyclopropyl
- R 3 F, H, Cl, Br, I
- R 4 F, H, Cl, Br, I
- the Applicant has now fully described his invention, which consists of the novel type of a NMDA antagonist described as a current dependent NMDA antagonist, methods to identify such current dependent NMDA antagonists, a method to design such current dependent NMDA antagonists, and the properties, advantages and uses of such current dependent NMDA antagonists. Furthermore, the Applicant has disclosed the structures of molecules which likely are current dependent NMDA antagonists with highly desirable properties, making them excellent candidates for therapeutic drugs and diagnostic agents. Any person ordinarily skilled in the art can now obtain current dependent NMDA antagonists according to the instant invention and use them as much improved replacements for previously known NMDA antagonists.
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Abstract
Current dependent NMDA antagonists block NMDA ion channels only under pathological, but not under physiological conditions. This leads to drugs with improved therapeutic properties.
Description
Description CURRENT DEPENDENT NMDA ANTAGONISTS
[1] Many NMDA antagonists with different molecular structures have been described in the scientific and patent literature, and much work has been devoted to develop novel and improved compounds which act as NMDA antagonists.
[2] In this disclosure, the expression "NMDA antagonist" refers to non-competitive channel blocking NMDA antagonists. The competitive NMDA antagonist, which competes with glutamate for its binding site at the NMDA receptor, is an other type of NMDA antagonist, which however is not relevant for this disclosure.
[3] The non-competitive open channel blocking NMDA antagonists to which this invention refers have a binding site inside the NMDA receptor ion channel. It is thought that they can access this binding site only when the channel is opened. Therefore, they are described as use dependent NMDA antagonists. Unless the channel is used and opened, they cannot access the binding site.
[4] In studies to develop new NMDA antagonists, the pivotal test for the quality of a compound was considered to be its ability to displace a high affinity radioligand, usually [3H]TCP or [3H](+)-MK-801, from the binding site. The higher its affinity for this binding site, the lower the IC value, the better a compound was thought to be as a NMDA antagonist and the more suitable as candidate for a drug. A number of such high affinity NMDA antagonists (aptiganel and gacyclidine for example) have been tested in clinical trials, and the results were very disappointing. There is now a paradigm shift towards the use of low affinity NMDA antagonists such as memantine. A thorough and recent review of the current knowledge about NMDA antagonists and their clinical applications can be found in Nat Rev Drug Discov. 5(2): 160-70, 2006 (PMID: 16424917). There is clearly a need for new and improved NMDA antagonists which have improved therapeutic properties.
[5] The Applicant has reviewed thoroughly the available literature on NMDA antagonists and has found one compound particularly interesting: (4a/?,9aS)-N-ethyl- 2,3,4,4a,9,9a-hexahydro-lH-fluoren-4a-amine. The pharmacological data of this compound, the primary and N-methyl amine analog, and (+)-MK-801 are disclosed in J Med Chem. 19;36(6):654-70, 1993 (PMID: 8459395). As can be seen in the table below, the affinity of the N-ethyl compound for the binding site is 5.7 times lower than that of the N-methyl analog, 4.1 times lower than that of the primary amine, and 18.9 times lower than that of (+)-MK-801. However, in the glutamate stimulated Ca + influx test, it is the second most potent compound, surpassed only slightly by (+)-MK-801. It also has high potency in the NMDA lethality test. Thus, while it has much lower affinity for the binding site, it has equal biological activity with compounds with much
higher affinity for the binding site. Therefore, the biological activity is independent from the affinity for the binding site. This finding is counter-intuitive and surprising. The Applicant has therefore sought an explanation for this surprising finding, which the authors of the original study ignored.
[6] Using molecular modeling studies, the Applicant has found the following explanation: these 4a-hexahydrofluorenamines bind to the binding site on the inside wall of the NMDA receptor ion channel in such a way that the substituent on the nitrogen extends out into the open channel and blocks it for Ca2+ ions. There is a critical size of the N-substituent which the channel can accommodate. Under normal, physiological conditions, the channel opens to such a width that the hydrogen and methyl substituted amines can easily enter the channel and bind to the binding site. Therefore, they have the highest affinity for the binding site under normal, physiological conditions as found when using brain membranes prepared according to standard methods, which are described in detail in the above publication. The N-ethyl substituent is too large for the normally opened channel, this compounds can not enter the channel efficiently, therefore there is a sharp drop in displacement of [3H]TCP. However, when the ion channel opens wider than under normal conditions, such as when testing for glutamate stimulated Ca + influx or NMDA lethality, the width of the channel is so large that it can also accommodate the larger N-ethyl substituent. This compound then enters the channel easily and binds to the binding site with high affinity. Therefore, it has high activity in the biological tests. Furthermore, since the hydrogen and methyl substituted amines do not block the open space of the widely opened channel as efficiently as the ethyl substituted compound when it is opened very widely, they are less efficient in inhibiting glutamate stimulated Ca influx.
[7] When further analyzing the method used in the above publication for the determination of the displacement of [3H]TCP, it becomes apparent that the method for the preparation of the brain membranes must have removed all glutamate from the brain membranes bearing NMDA receptors. However, in the absence of glutamate, the NMDA receptor ion channel is in the closed state. It appears therefore that these high
affinity NMDA antagonists can access the binding site inside of the NMDA receptor ion channel even in the closed state. This would be possible if the NMDA receptor ion channel has a funnel shape, and the PCP binding site is located in the upper, wide section of the funnel, which is accessible for small molecules even when the ion channel is in the closed state. Thus, using standard methods for the selection of NMDA antagonists by optimizing for highest binding site affinity in the absence of glutamate, closed channel binding NMDA antagonists were selected. Closed channel binding NMDA antagonists are not use or current dependent and will necessarily be unsuitable as therapeutic agents.
[8] The diameter of the opening of the channel is dependent on the NMDA agonist concentration and determines the current that flows through the channel. For a higher current to flow, the channel must be opened wider. Therefore, those NMDA antagonists which can access the channel and bind to the binding site inside the channel only above a certain width of opening, or above a certain current flowing through the NMDA receptor ion channel, but not below a certain width of opening, or below a certain current flowing through the NMDA receptor ion channel, can be described as current dependent NMDA antagonists. Their affinity for the binding site remains essentially the same, but they do not gain access to the binding site, so their affinity appears lower when they are tested under low glutamate conditions, or in the absence of glutamate. The ability of a current dependent NMDA antagonist to access the binding site is dependent on the opening width of the ion channel, or the current flowing through the ion channel, and such a current dependent NMDA antagonist will therefore block higher currents more than lower currents.
[9] Alternatively, such current dependent NMDA antagonists may be able to bind to the binding site in two different conformations: one conformation with low affinity for the binding site in which a flexible substituent extends along the ion channel opening, and one conformation with high affinity for the binding site where this substituent extends out into the opening of the ion channel. The molecule will then adopt the configuration which the width of the channel permits. If the width of the opening of the ion channel is large enough for the molecule to adopt the high affinity configuration, it will bind with high affinity to the binding site and efficiently block the current through the ion channel. Else it will bind in the low affinity conformation and have less blocking effect on the current. Therefore, dependent on the opening width of the ion channel, or the current flowing through the ion channel, a current dependent NMDA antagonist may bind to the binding site in a low and a high affinity conformation and block higher currents more than lower currents.
[10] Such current dependent NMDA antagonists will block the NMDA receptor ion channel more above a certain current threshold, and much less below a certain current
threshold. This has the advantage that only high currents of pathologically active NMDA receptors are blocked very efficiently due to the high affinity for the binding site, while currents of normally active NMDA receptors remain unaffected, because the NMDA antagonist can't access its binding site or has low affinity for the binding site. An additional advantage is that current dependent NMDA antagonists will block the wide open channel more completely due to their size, which fills the wide open channel, while previously known NMDA antagonists optimized for high affinity under normal conditions, or even for closed channel affinity, are too small to completely block the wide open channel. These advantageous properties of current dependent NMDA antagonists are expected to lead to drugs with high therapeutic activity against pathologically active NMDA receptors while largely eliminating the side effects caused by blocking normally active NMDA receptors.
[11] The currently known high affinity NMDA antagonists do not show such current dependency in the blocking effect on the NMDA receptor. They block normally, physiologically active NMDA receptors as efficiently as, or actually more efficiently than, pathologically over-active NMDA receptors and therefore cause a variety of side effects which make them unsuitable for clinical application. Memantine is a noteworthy exception since it also shows current dependency, but what causes its current dependency seems unclear, and it also does not bind to the PCP binding site. Its mechanism of current dependency is likely different from that of the disclosed current dependent NMDA antagonists. A disadvantage of memantine is that it does not efficiently block over-active NMDA receptors, but only gradually reduces the current.
[12] The previously practiced selection of NMDA antagonists for highest affinity for the binding site under physiological conditions, or even for closed channel binding site affinity, inevitably selected for the compounds with the worst therapeutic properties, because NMDA antagonists selected by this method will block all normally active NMDA receptors and therefore lead to severe side effects. Moreover, they do not efficiently block NMDA receptors under high, pathological glutamate concentrations, and therefore are not effective therapeutic agents. Current dependent NMDA antagonists, due to their selectivity for pathologically active NMDA receptors, have good chances of succeeding where previously tested NMDA antagonists have failed. Since such current dependent NMDA antagonists will efficiently block over-currents through NMDA receptors, but not normal currents, they may also constitute novel and valuable therapeutic agents for the treatment of epilepsy.
[13] Since such current dependent NMDA antagonists will only bind to pathologically active NMDA receptors, but not to normally active NMDA receptors, they furthermore constitute valuable imaging agents to locate pathologic activity in the brain. They are therefore also very useful as diagnostic agents.
[14] Such current dependent NMDA antagonists are therefore valuable therapeutics and diagnostics with much improved properties over previously known NMDA antagonists, and it would be desirable to have methods available to identify such current dependent NMDA antagonists. The Applicant has therefore devised methods which allow the identification of such current dependent NMDA antagonists.
[15] A first method to identify current dependent NMDA antagonists consists in measuring the affinity of a compound for the PCP binding site of the NMDA receptor at different concentrations of a NMDA agonist. Those compounds which show a lower affinity for the binding site when the NMDA agonist concentration is lower, and a higher affinity for the binding site when the NMDA agonist concentration is higher, are current dependent NMDA antagonists. Preferably, the NMDA agonist used is glutamate, and the lower concentration of the NMDA agonist glutamate is the concentration found under normal, physiological conditions, while the higher concentration of the NMDA agonist glutamate used is the concentration found under pathological conditions, under which the NMDA receptor needs to be blocked. The lower the affinity of a compound under normal conditions, and the higher the affinity under pathological conditions, the better is this compound suited as drug candidate. However, it should be noted that there may well exist current dependent NMDA antagonists which do not bind to the PCP binding site, but to an other binding site inside the NMDA receptor channel. These current dependent NMDA antagonists can not very well be identified using this method.
[16] A second method to identify current dependent NMDA antagonists consists in measuring the effect of a compound on the NMDA agonist induced current through the NMDA receptor ion channel. Those NMDA antagonists which are reducing or blocking currents more above a certain threshold, or above a certain concentration of the NMDA agonist, and less below a certain threshold, or below a certain concentration of the NMDA agonist, are current dependent NMDA antagonists. Preferably, the NMDA agonist used to induce the NMDA receptor current is glutamate, and the lower concentration of the NMDA agonist glutamate is the concentration found under normal, physiological conditions, while the higher concentration of the NMDA agonist glutamate used is the concentration found under pathological conditions, under which the NMDA receptor needs to be blocked. The lower the current blocking effect of a compound under normal conditions, and the higher the current blocking effect under pathological conditions, the better is this compound suited as drug candidate. This is the best and most conclusive method to identify and characterize current dependent NMDA antagonists. It will also reliably identify current dependent NMDA antagonists which do not bind to the PCP binding site. This method furthermore allows to determine the exact characteristics of a current
dependent NMDA antagonist by making multiple measurements at multiple concentrations of the NMDA agonist.
[17] A third method to identify current dependent NMDA antagonists consists in measuring the NMDA agonist dependent Ca2+ influx into cells bearing a NMDA receptor at different concentrations of a NMDA agonist. Those NMDA antagonists which are reducing or blocking the NMDA agonist dependent Ca2+ influx into cells more at a higher concentration of the NMDA agonist, and less at a lower concentration of the NMDA agonist, are current dependent NMDA antagonists. Preferrably, the NMDA agonist used to induce the NMDA agonist dependent Ca influx into cells is glutamate, and the lower concentration of the NMDA agonist glutamate is the concentration found under normal, physiological conditions, while the higher concentration of the NMDA agonist glutamate used is the concentration found under pathological conditions, under which the NMDA receptor needs to be blocked. The lower the Ca2+ influx blocking effect of a compound under normal conditions, and the higher the Ca + influx blocking effect under pathological conditions, the better is this compound suited as drug candidate.
[18] A fourth method to identify current dependent NMDA antagonists consists in measuring the 5-HT2A agonist facilitated NMDA receptor current in the presence of a test compound. The facilitation of NMDA currents by 5-HT2A agonists has been disclosed by Arvanov et al. in Eur J Neurosci. 1999 Aug;l l(8):2917-34, 1999 (PMID: 10457188) and Eur J Neurosci. ll(9):3064-72, 1999 (PMID: 10510170). Further information on 5-HT2A agonist facilitated NMDA currents can be found in Lambe EK, Aghajanian GK, Hallucinogen-Induced UP States in the Brain Slice of Rat Prefrontal Cortex: Role of Glutamate Spillover and NR2B-NMDA Receptors. Neuropsy- chopharmacology. 2005 Nov 2; [Epub head of print] (PMID: 16292328). The normal and the 5-HT2A agonist facilitated NMDA receptor currents are recorded according to the methods described in these publications in the presence and absence of a NMDA antagonist. Those compounds which have little or no influence on normal NMDA receptor currents, but strongly limit or block 5-HT2A agonist facilitated NMDA receptor currents are current dependent NMDA antagonists. The lower the current blocking effect of a compound on normal NMDA receptor currents, and the higher the current blocking effect on 5-HT2A agonist facilitated currents, the better is this compound suited as drug candidate. Any compound identified as a current dependent NMDA antagonist by this method needs to be tested with other methods to verify that it is actually a NMDA receptor antagonist and does not only antagonize the effects of the 5-HT2A agonist.
[19] A fifth method to identify current dependent NMDA antagonists consists in measuring the neuroprotective activity of a compound against the neurotoxicity of high
concentrations of a NMDA agonist. Those compounds which have relatively low affinity for the PCP binding site, but comparatively high activity against the toxicity of the NMDA agonist are current dependent NMDA antagonists. Those compounds which have very high neuroprotective potency, but only very modest binding affinity for NMDA receptors when measured under low glutamate concentrations of in the absence of glutamate, are the most suitable drug candidates. Since mechanisms other than NMDA antagonism can cause neuroprotection, it needs to be verified with other methods that compounds identified with this method actually act as current dependent NMDA antagonists.
[20] Data according to this fifth method disclosed in J Med Chem. 36(14): 1938-46, 1993
(PMID: 8101572) indicate that (+)-N-methyl-IDDC,
(+)-N-methyl-10,5-(iminomethano)-10,l l-dihydro-5H-dibenzo[α, J]cycloheptene, is a current dependent NMDA antagonist. (+)-N-methyl-IDDC has a 22-fold lower affinity for the binding site than (+)-K)DC, (+)-10,5-(iminomethano)-10,ll-dihydro-5H- dibenzo[α,J]cycloheptene, but it is almost as effective as a neuroprotective agent. The authors noticed this surprising fact and wondered about it, but they did not offer a conclusive explanation.
[21] These different methods to identify a current dependent NMDA antagonist may be usefully combined. The first method described may be used, for example, for the initial screening of a large number of different compounds, because it can be performed quickly and cheaply and gives a good first indication of the current dependency of a NMDA antagonist. Those compounds which give an indication of current dependency using this method may then be further investigated using the second method to fully characterize the current dependent NMDA antagonistic properties of the compound.
[22] The technical methods for performing the measurements used in these methods to identify current dependent NMDA antagonists are extensively documented in the scientific literature and require no further explanation to those skilled in the art.
[23] It would now be desirable to have promising candidates of current dependent
NMDA antagonists available for testing by the disclosed methods. The Applicant has therefore devised a method to design current dependent NMDA antagonists.
[24] Any known NMDA antagonist binding to the PCP binding site of the NMDA receptor with reasonably high affinity may be modified to become a current dependent NMDA antagonist by increasing the size of the molecule to such a size that it can not access the inside of the closed or normally opened NMDA receptor ion channel any more, but can still access it when it is excessively opened. Starting with the molecule with the highest affinity for the binding site under normal conditions in a structural class, the size of the molecule is gradually increased in such a position where the additional bulk does not interfere with the binding to the binding site, but extends into
the open channel. The further this additional bulk extends out into the open channel, the higher is the threshold current where the switch from apparent low affinity to apparent high affinity occurs. This principle can be easily seen in the above mentioned series of 4a-hexahydrofluorenamines. By further increasing the size of the N- substituent to propyl, a compound with an even higher threshold current would be obtained. However, N-propyl adds a full CH group to the length of the chain, and this might lead to a threshold current which is already too high. A more gradual increase in the length of the chain by using the series ethyl, isopropyl (which is essentially equivalent to ethyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl might therefore be a better strategy to find a compound with the desired threshold current. Furthermore, through molecular modeling studies it was discovered that the N- substituent should be a rigid cycloalkyl rather than a flexible alkyl group, to ascertain that it extends into the channel and does not align along the channel. Such alignment will happen if the N-substituent is too large to extend into the channel and will cause a drop in affinity for the binding site. Such NMDA antagonists only have reduced affinity, their affinity is however not current dependent. N-Butyl-1-phenylcyclo- hexylamine for example has both lower affinity for the PCP site and lower biological activity than PCP. The butyl group is much too large to extend into the channel of a normally opened NMDA receptor, and if this compound was a current dependent NMDA antagonist, its threshold current would be so high that it would be without any effect under normal, physiological conditions. But since the butyl chain can also align along the channel, it still has about one third the potency of PCP in behavioral tests. N- Ethyl- and N-isopropyl-1-phenylcyclohexylamine, however, also have much lower affinity for the PCP site, but their potency in behavioral tests is equal to or higher than that of PCP. Therefore, these compounds have more difficulty accessing the binding site, but once they are at the binding site, they bind with high affinity. Thus, they may be described as current dependent NMDA antagonists with a threshold current which is easily reached by normally active NMDA receptors. These data can be found in Neuropharmacology 21(12): 1329-36, 1982 (PMID: 7155312). Using (R)- and (S)-2-butyl, - 2-but-3-ene and -2-but-3-yne as substituent of the 4a-hexahydrofluorenamine, it will be possible to glean further insight into the shape requirements for current dependent NMDA antagonists.
[25] Examples of some potential current dependent NMDA antagonists designed according to this method are given below:
[27] R = ethyl, isopropyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, (R)- and (S)-2-butyl, (R)- and (S)-2-but-3-ene, (R)- and (S)-2-but-3-yne. [28] R = aryl, preferably phenyl, 2-thienyl, 2-toluyl, 2-chlorophenyl, 3-hydroxyphenyl,
3-aminophenyl, 2-methyl-5-hydroxyphenyl, 2-methyl-5-aminophenyl,
2-chloro-5-hydroxyphenyl, 2-chloro-5-aminophenyl. [29] R2 = H, CH3
[30] R3 = H, NH2, OH
[31] X = -CH 2 -, -CH 2 CH 2 -, -O-, -S-, -CH 2 O-, -CH 2 S-
[32] As mentioned above, (+)-N-methyl-IDDC shows very interesting properties indicating that it is a current dependent NMDA antagonist. It is also a highly rigid molecule where every substituent is held in a precisely defined position. Furthermore, the compound with the highest affinity for the binding site in this series, 3-fluoro-(+)-IDDC, has excellent affinity, with an IC 50 of 15.5 nM against [3H]
(+)-MK-801. Therefore, in addition to 1-aryl-cyclohexylamines and 4a-hexahydrofluorenamine and their derivatives, (+)-IDDC serves as an excellent and preferred starting point for the development of current dependent NMDA antagonists.
[33] Detailed information on (+)-N-methyl-IDDC can be found in J Med Chem.
36(14): 1938-46, 1993 (PMID: 8101572) and in patent US 5688789, which is included in this disclosure by reference. In the J Med Chem paper, an IC of 826 nM against [3H]-(+)-MK-801 is given, and the IC was determined in the presence of 1 μM glutamate. In the presence of 1 μM glutamate, the NMDA receptor ion channel is not opened wide enough to accomodate the molecule, therefore it has a low affinity for the binding site. From the data presented below, it can be expected that above a glutamate concentration of about 3 μM, (+)-N-methyl-IDDC will have high affinity for the binding site.
[34] By analyzing figure 1 of patent US 5688789, additional information can be deduced. It can be seen that a glutamate concentration of up to 3 μM is not toxic, because at this concentration cell survival is not reduced. However, above a glutamate concentration of about 3 μM, the cell survival starts to drop significantly.
[35] Therefore, glutamate concentrations up to about 3 μM are normal, physiological glutamate concentrations, while glutamate concentrations above 3 μM are toxic, pathological glutamate concentrations. This is useful information when identifying current dependent NMDA antagonists according to the methods disclosed. The threshold glutamate concentration where the current dependent NMDA antagonist gains access to the binding site should therefore be around 3 μM. Apparently, (+)-N-methyl-IDDC has its threshold around this desirable level.
[36] It can furthermore be seen from this figure that (+)-IDDC is actually neurotoxic
under low glutamate concentrations. At 3 μM glutamate, the cell survival is reduced in the presence of (+)-IDDC, but not in the absence of (+)-IDDC. N-Methyl-IDDC does not show such a neurotoxic effect. This can now be explained, because N- methyl-IDDC is a current dependent NMDA antagonist which does not block normally active NMDA receptors below a glutamate concentration of about 3 μM.
[37] In Lancet Neurol. l(6):383-6, 2002 (PMID: 12849400), Ikonomidou and Turski propose that NMDA receptor antagonists failed stroke and traumatic brain injury trials in human beings because blockade of synaptic transmission mediated by NMDA receptors hinders neuronal survival. Normal or slightly elevated glutamate concentrations promote survival, and blocking NMDA receptors under such physiological glutamate concentrations is harmful. This idea is clearly supported by the above data. Since current dependent NMDA antagonists will only block pathologically active NMDA receptors, but not normally active NMDA receptors, they do not hinder neuronal survival.
[38] Furthermore, the following information can be found in patent US 5688789:
[39] "Identical to MK-801 , (+)-N-methyl IDDC ( 10 μM) inhibited the NMDA current in a use-dependent and voltage-dependent manner. Serial applications evoked progressively smaller currents. Inhibition by (+)-N-methyl IDDC was reversed only with prolonged or repeated application of NMDA. The rate of recovery from blockade by (+)-N-methyl IDDC was somewhat more rapid than the rate of recovery of responses following MK-801. This observation is consistent with the observation that (+) N- methyl IDDC has a lower affinity than MK-801 for the PCP receptor."
[40] This is a further indication that (+)-N-methyl-IDDC and its derivatives have highly desirable properties as current dependent NMDA antagonists. A rapid recovery from the blockage of NMDA receptors is an important factor to enable fast recovery from blockage when normal glutamate concentrations are restored. Rapid recovery from blockage enables the restorage of normal synaptic transmission, which is essential for neuronal survival.
[41] Further information on these compounds can be found in patents GB 1146109 and
CH 510684, which are included in this disclosure by reference. These patents disclose derivatives of IDDC as anticonvulsants and muscle relaxants. It is well known that NMDA antagonists have anticonvulsant and muscle relaxant effects. While N- and 10-substituted derivatives of IDDC are claimed as anticonvulsants and muscle relaxants, IDDC itself is specifically excluded in GB 1146109. Apparently, the authors have found IDDC unsuitable as drug, and this can now be explained easily: IDDC is not a current dependent NMDA antagonist and therefore unsuitable for therapeutic applications. As can be seen from the data disclosed in these patents, this series of compounds also has very good oral bioavailability, which is very advantageous. Useful
dose ranges for human beings are also disclosed in patent GB 1146109, and it appears therefore that these drugs have been tested in human beings already and were found to be tolerable and to have useful therapeutic properties. These compounds are, however, not just anticonvulsants and muscle relaxants, but valuable current dependent NMDA antagonists.
[42] Accordingly, in addition to the nitrogen of (+)-IDDC, the 10-position of (+)-IDDC is an additional attractive site for adding bulk to the parent molecule. Molecular modeling studies also show that the substituents on the nitrogen and the 10-position extend in the same direction, apparently into the open channel. A fluorine in the 3-position of (+)-IDDC has been shown to increase affinity, and it will likely have a positive effect on the metabolic stability of the drug. 3,7-Difluoro-(+)-IDDC has only slightly reduced affinity (racemate 51.2 nM, estimated for (+)-enantiomer 26 nM compared to 15.5 nM for 3-fluoro-(+)-IDDC), but can be expected to have even better metabolic stability. Reducing the affinity somewhat may also have a positive effect on the recovery rate. Using 18F as fluorine substituent, compounds suitable as imaging agents can be obtained. With this information at hand, the following molecules can be designed as current dependent NMDA antagonists with particularly favorable and useful properties:
[43] Wherein:
[44] R = H, methyl, ethyl, isopropyl, allyl, propargyl, cyclopropyl, cyclobutyl, cy- clopentyl, cyclohexyl, adamantyl, (R)- and (S)-2-butyl, (R)- and (S)-2-but-3-ene, (R)- and (S)-2-but-3-yne
[45] R = H, methyl, ethyl, isopropyl, cyclopropyl
[46] R3 = F, H, Cl, Br, I
[47] R 4 = F, H, Cl, Br, I
[48] provided that R and R are not simultaneously hydrogen.
[49] Particularly preferred compounds are:
[50] (+)-N-Methyl-10,5-(iminomethano)-10,ll-dihydro-5H-dibenzo[α,J]cycloheptene
[51 ] (+)- 10-Methyl- 10,5-(iminomethano)- 10, 11 -dihydro-5H-dibenzo[α, J]cycloheptene
[52] (+)-N, 10-Dimethyl-10,5-(iminomethano)-10,ll-dihydro-5H-dibenzo[α,J] cy-
cloheptene [53] (+)-3-Fluoro-N-methyl-10,5-(iminomethano)-10,ll-dihydro-5H-dibenzo[α,J]cyclo heptene [54] (+)-3-Fluoro- 10-methyl- 10,5-(iminomethano)- 10, 11 -dihydro-5H-dibenzo[α, J]cyclo heptene [55] (+)-3-Fluoro-N, 10-dimethyl-10,5-(iminomethano)-10,l l-dihydro-5H-dibenzo[α, d] cycloheptene
[56] (+)-N-Ethyl- 10,5-(iminomethano)- 10, 11 -dihydro-5H-dibenzo[α, J]cycloheptene
[57] (+)-N-Ethyl- 10-methyl- 10,5-(iminomethano)- 10, 11 -dihydro-5H-dibenzo[α,J]cyclo heptene [58] (+)-3-Fluoro-N-ethyl-10,5-(iminomethano)-10,ll-dihydro-5H-dibenzo[α,J]cyclohe ptene [59] (+)-3-Fluoro-N-ethyl- 10-methyl- 10,5-(iminomethano)- 10, 11 -dihydro-5H-dibenzo[α
,d] cycloheptene [60] (+)-3,7-Difluoro-N-ethyl-10,5-(iminomethano)-10,ll-dihydro-5H-dibenzo[α,J]cycl oheptene [61] (+)-3,7-Difluoro-N-ethyl-10-methyl-10,5-(iminomethano)-10, 1 l-dihydro-5H-diben zo[α,J]cycloheptene
[62] (+)-N-Isopropyl-10,5-(iminomethano)-10,ll-dihydro-5H-dibenzo[α,J]cycloheptene
[63] (+)-N-Isopropyl- 10-methyl- 10,5-(iminomethano)- 10, 11 -dihydro-5H-dibenzo[α, d]cy cloheptene [64] (+)-3-Fluoro-N-isopropyl- 10,5-(iminomethano)- 10, 11 -dihydro-5H-dibenzo[α,J]cyc loheptene [65] (+)-3-Fluoro-N-isopropyl- 10-methyl- 10,5-(iminomethano)- 10, 11 -dihydro-5H-diben zo[α,J]cycloheptene [66] (+)-3,7-Difluoro-N-isopropyl-10,5-(iminomethano)-10,ll-dihydro-5H-dibenzo[α,J] cycloheptene [67] (+)-3,7-Difluoro-N-isopropyl- 10-methyl- 10,5-(iminomethano)- 10, 11 -dihydro-5H-d ibenzo[α,J]cycloheptene [68] (+)-N-Cyclopropyl-10,5-(iminomethano)-10, 1 l-dihydro-5H-dibenzo[α,J]cyclohept ene [69] (+)-N-Cyclopropyl-l 0-methyl- 10,5-(iminomethano)- 10, 1 l-dihydro-5H-dibenzo[α,J
] cycloheptene [70] (+)-3-Fluoro-N-cyclopropyl- 10,5-(iminomethano)- 10, 11 -dihydro-5H-dibenzo[α,J]c ycloheptene [71] (+)-3-Fluoro-N-cyclopropyl- 10-methyl- 10,5-(iminomethano)- 10, 11 -dihydro-5H-dib enzo[α,J]cycloheptene [72] (+)-3,7-Difluoro-N-cyclopropyl-10,5-(iminomethano)-10,ll-dihydro-5H-dibenzo[α
,J]cycloheptene
[73] (+)-3,7-Difluoro-N-cyclopropyl- 10-methyl- 10,5-(iminomethano)- 10, 11 -dihydro-5H
-dibenzo [a,d] cycloheptene
[74] The above compounds, where the 10-methyl group is replaced by a 10-ethyl group.
[75] The above compounds, where the 10-methyl group is replaced by a 10-isopropyl group.
[76] The above compounds, where the 10-methyl group is replaced by a 10-cyclopropyl group.
[77] The most preferred compounds are:
[78] (+)-3,7-Difluoro-N-methyl-10,5-(iminomethano)-10,ll-dihydro-5H-dibenzo[α,J]cy cloheptene
[79] (+)-3,7-Difluoro-10-methyl-10,5-(iminomethano)-10,ll-dihydro-5H-dibenzo[α,J]c ycloheptene
[80] (+)-3,7-Difluoro-N, 10-dimethyl-10,5-(iminomethano)-10,l l-dihydro-5H-dibenzo[ a,d] cycloheptene
[81] The presented data indicate that these three compounds will be ideal therapeutics for all conditions caused by pathologically active NMDA receptors and valuable imaging agents to locate pathologically active NMDA receptors. Which one of these three has the best therapeutic properties needs to be determined experimentally.
[82] These compounds can be synthesized according to the methods described in the mentioned publications and patents.
[83] The Applicant has now fully described his invention, which consists of the novel type of a NMDA antagonist described as a current dependent NMDA antagonist, methods to identify such current dependent NMDA antagonists, a method to design such current dependent NMDA antagonists, and the properties, advantages and uses of such current dependent NMDA antagonists. Furthermore, the Applicant has disclosed the structures of molecules which likely are current dependent NMDA antagonists with highly desirable properties, making them excellent candidates for therapeutic drugs and diagnostic agents. Any person ordinarily skilled in the art can now obtain current dependent NMDA antagonists according to the instant invention and use them as much improved replacements for previously known NMDA antagonists.
[84] The Applicant would have liked to support his theoretical considerations with experimental data. Unfortunately, the Applicant does not currently have the means to conduct the necessary experiments.
Claims
[ 1 ] The method of identifying current dependent NMDA antagonists by measuring the affinity of a compound for the PCP binding site of the NMDA receptor in the presence of a lower and in a higher concentration of glutamate or NMDA or an other agonist at the NMDA receptor. Those compounds which show a higher affinity for the binding site in the presence of a higher NMDA agonist concentration than in the presence a lower NMDA agonist concentration are current dependent NMDA antagonists.
[2] The method of identifying current dependent NMDA antagonists by measuring the NMDA agonist dependent current through the NMDA receptor ion channel. Those NMDA antagonists which are reducing or blocking currents more above a certain current threshold, or above a certain concentration of the NMDA agonist, and less below a certain current threshold, or below a certain concentration of the NMDA agonist, are current dependent NMDA antagonists.
[3] The method of identifying current dependent NMDA antagonists by measuring the NMDA agonist dependent Ca + influx into cells bearing a NMDA receptor. Those NMDA antagonists which inhibit the Ca + influx more in the presence of higher NMDA agonist concentrations, and less in the presence of a lower NMDA agonist concentrations, are current dependent NMDA antagonists.
[4] The method of identifying current dependent NMDA antagonists by measuring the 5-HT2A agonist facilitated NMDA receptor current. Those NMDA antagonists which reduce or block the 5-HT2A agonist facilitated NMDA receptor current, but do not reduce or block the normal NMDA receptor current, are current dependent NMDA antagonists.
[5] The method of identifying current dependent NMDA antagonists by measuring the neuroprotective activity of a compound against the neurotoxicity of high concentrations of a NMDA agonist. Those compounds which have relatively low affinity for the PCP binding site, but comparatively high activity against the toxicity of the NMDA agonist are current dependent NMDA antagonists.
[6] The use of current dependent NMDA antagonists as improved therapeutics for all therapeutic applications which are known for NMDA antagonists, including, but not limited to, the treatment of Alzheimer's disease, neurodegenerative diseases, Parkinson's disease, spasticity, schizophrenia, stroke, cerebral trauma and hypoxia, neuropathic pain, and as neuroprotective therapeutics.
[7] The method of treating epilepsy with a current dependent NMDA antagonist.
[8] The method of locating pathologically active NMDA receptors in the brain by using current dependent NMDA antagonists as imaging agents.
[9] The use of a current dependent NMDA antagonist in combination with a
5-HT2A agonist according to patent application PCT/IB2006/051080 by the same Applicant.
[10] The method of designing current dependent NMDA antagonists by increasing the molecular size of a known NMDA antagonist in such a way that it excludes its access to the binding site inside of the NMDA receptor ion channel when the channel is opened to such a degree as found under normal, physiological conditions, but still allows its access to the binding site when the NMDA receptor ion channel is opened excessively under abnormal, pathological conditions. Steric bulk is added to a known NMDA antagonist in such a way that it does not interfere with the binding to the binding site, but extends into the open channel.
[11] The use according to claims 6 to 9 of current dependent NMDA antagonists obtained according to the method of claim 10.
[12] The method of designing current dependent NMDA antagonists by adding steric bulk as substituents on the nitrogen and/or the 10-position of (+)-10,5-(iminomethano)-10,l l-dihydro-5H-dibenzo[α,J]cycloheptene, and optionally adding fluorine substituents at the 3- and/or 7-positions of this molecule.
[13] The use according to claims 6 to 9 of current dependent NMDA antagonists obtained according to the method of claim 12.
[14] The use of (+)-3,7-difluoro-N-methyl-10,5-(iminomethano)-10,l l-dihydro-5H - dibenzo[α, J]cycloheptene and its salts as current dependent NMDA antagonist according to claims 6 to 9.
[15] The use of (+)-3,7-difluoro-10-methyl-10,5-(iminomethano)-10,l l-dihydro-5H - dibenzo[α,J]cycloheptene and its salts as current dependent NMDA antagonist according to claims 6 to 9.
[16] The use of (+)-3,7-difluoro-N,
10-dimethyl- 10,5-(iminomethano)- 10, 11 -dihydro-5H-dibenzo[α, J]cycloheptene and its salts as current dependent NMDA antagonist according to claims 6 to 9.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IB2006/051783 WO2007141600A1 (en) | 2006-06-04 | 2006-06-04 | Current dependent nmda antagonists |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IB2006/051783 WO2007141600A1 (en) | 2006-06-04 | 2006-06-04 | Current dependent nmda antagonists |
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|---|---|
| WO2007141600A1 true WO2007141600A1 (en) | 2007-12-13 |
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| PCT/IB2006/051783 WO2007141600A1 (en) | 2006-06-04 | 2006-06-04 | Current dependent nmda antagonists |
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| WO (1) | WO2007141600A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011085213A3 (en) * | 2010-01-07 | 2011-09-15 | Sanford-Burnham Medical Research Institute | Pathologically-activated therapeutics |
| CN115286626A (en) * | 2016-06-13 | 2022-11-04 | 国家健康与医学研究院 | Novel dezocyclopine derivatives as peripheral NMDA receptor antagonists |
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| US5688789A (en) * | 1989-04-14 | 1997-11-18 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon | PCP receptor ligands and the use thereof |
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| US5688789A (en) * | 1989-04-14 | 1997-11-18 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon | PCP receptor ligands and the use thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011085213A3 (en) * | 2010-01-07 | 2011-09-15 | Sanford-Burnham Medical Research Institute | Pathologically-activated therapeutics |
| CN115286626A (en) * | 2016-06-13 | 2022-11-04 | 国家健康与医学研究院 | Novel dezocyclopine derivatives as peripheral NMDA receptor antagonists |
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