Classifications

• • 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
  • A61K31/16—Amides, e.g. hydroxamic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to the treatment of psychiatric disorders and more particularly bipolar disorders.
• Bipolar disorder or manic-depressive illness, is a common condition with a life-time prevalence of 1-2% [Weissman, M. M., Leaf, P. J., Tischler, G. L., Blazer, D. G., Karno, M., Bruce, M. L., Florio, L. P. 1988. Affective disorders in five United States communities. Psychol Med 18:141-53]. Its episodic course with intervening full recovery belies the severe impact of this disorder. The cumulative effects of recurring bouts of mania and depression lead to an increased rate of marital and family breakdown, unemployment, impaired career progress and consequent financial difficulties. About 15% of bipolar patients commit suicide, and mortality rates due to physical disorders are also increased [Angst J, Clayton P.
• VPA branched chain fatty acid - valproic acid
• Inositol biosynthesis Inositol (I) is synthesized de novo in two steps.
• the first step the conversion of glucose-6-phosphate (glucose-6-P) to inositol- 1 -phosphate (I-l-P), is catalyzed by wjvo-inositol-1 -phosphate (MIP) synthase.
• MIP wjvo-inositol-1 -phosphate
• the second step of the pathway is the conversion of I-l-P to inositol by myo- inositol monophosphatase (IMPase). This step is common to the production of inositol via the de novo synthetic pathway and its recycling in the phosphatidylinositol (PI) cycle.
• PI phosphatidylinositol
• VPA like lithium, causes inositol depletion in yeast [Vaden DL, Ding D, Peterson B,
• U.S. patent No. 6,555,585 discloses a method for the treatment of mania in bipolar disorder using derivatives of VPA and 2-valproenic acid.
• the anti- manic effect of the compounds was evaluated using the amphetamine-induced hyperactivity model. This model focuses on an induced increase in the activity level of the animal as parallel to the hyperactivity in the manic patient.
• the reversal of the induced hyperactivity in rodents, by pretreatment with a drug indicates the possible efficacy of the drag in the treatment of human mania.
• the compounds disclosed in U.S. patent No. 6,555,585 are disadvantageous since they were found to be effective mainly for treating the manic phase in bipolar disease.
• VPA a broad spectrum antiepileptic drug useful also for treating bipolar disorders (both mania and depression) is limited by its considerable adverse effects including hepatotoxicity and teratogemcity and thus cannot be given to women of childbearing age and children [Bailie, T. A. et al. In Antiepileptic Drags, eds. R.H. Levy et al. Raven Press, New York. Pp. 641-651 (1989)].
• U.S. patent No. 5,880,157 discloses derivatives of 2,2,3,3 tetramethylcyclopropane carboxylic acid for treating epilepsy.
• Isoherranen N. et al 2002 studied the anticonvulsant activity of N-methyl- tetramethylcyclopropyl carboxamide (M-TMCD) and its metabolite in various animal (rodent) models of human epilepsy, and evaluated their ability to induce neural tube defects (NTDs) and neurotoxicity.
• NTDs neural tube defects
• M- TMCD (a cyclopropyl analog of VPA) was found to be advantageous compared to VPA because of its better potency as an anticonvulsant drag, its wider safety of margin, its lack of teratogenicity and its potential lack of hepatotoxicity.
• the present invention relates to the use of a compound of formula I
• Ri and R 2 are the same or different and are independently selected from hydrogen and C ⁇ -C 6 alkyl group, for the preparation of a medicament for treating a psychiatric disorder.
• one of Ri or R 2 is C ⁇ -C 6 alkyl group and the other is hydrogen.
• the C C 6 alkyl group is a straight or a branched alkyl group.
• the Ci-C 6 alkyl group is a methyl group.
• the psychiatric disorder is a bipolar disorder.
• the compound is administered as a pharmaceutical composition comprising a compound of formula I and a pharmaceutical acceptable carrier.
• the route of administration of the compound is selected from the group consisting of oral, parenteral, topical, transdermal, rectal and buccal administration.
• the route of administration of the compound is selected from the group consisting of oral and parenteral administration.
• the parenteral route of administration is selected from the group consisting of intravenous, intramuscular, intraperitoneal and subcutaneous administration.
• the compound is administered in the range of from about 1 mg to about 1000 mg per day.
• the compound is administered in the range of from about 20 mg to about 500 mg per day.
• the present invention also relates to a method for treating a psychiatric disorder in a mammal comprising administering to the mammal, a therapeutically effective amount of a compound of formula I
• Rj and R 2 are the same or different and are independently selected from hydrogen and C C ⁇ alkyl group.
• one of Ri or R 2 is C ⁇ -C 6 alkyl group and the other is hydrogen.
• the - alkyl group is a straight or a branched alkyl group.
• the C C 6 alkyl group is a methyl group.
• the psychiatric disorder is a bipolar disorder.
• the mammal is a human.
• the c ompound o f formula I i s administered as a pharmaceutical c omposition comprising a compound of formula I and a pharmaceutical acceptable carrier.
• the route of administration is selected from the group consisting of oral, parenteral, topical, transdermal, rectal and buccal administration.
• the route of administration is selected from the group consisting of oral and parenteral administration.
• the parenteral route of administration is selected from the group consisting of intravenous, intramuscular, intraperitoneal and subcutaneous administration.
• the therapeutically effective amount is in the range of from about 1 mg to about 1000 mg per day.
• the therapeutically effective amount is in the range of from about 20 mg to about 500 mg per day.
• Ri and R 2 are the same or different and are independently selected from hydrogen and Ci-C 6 alkyl group.
• the present invention additionally relates to the use of a compound of formula I
• Ri and R 2 are the same or different and are independently selected from hydrogen and CpC ⁇ alkyl group, for the preparation of an inhibitor of MIP synthase.
• Ri and R 2 are the same or different and are independently selected from hydrogen and - alkyl group.
• M-TMCD refers equally to N-methyl-2,2,3,3- tetramethylcyclopropanecarboxamide; N-methyl-tetramethylcyclopropane carboxamide; and N-methyl-tetramethylcyclopropyl carboxamide.
• FIG. 2 illustrates the in-vitro effect of VPA on MIP synthase activity in human brain homogenate (Dixon's plot). Results are means + S.E.M.
• MIP myo-inositol-1 -phosphate
• VPA valproic acid
• Vo activity in the absence of VPA
• V VPA activity in the presence of the appropriate
• FIG. 3 illustrates a noncompetitive mode of inhibition of MIP synthase by VPA (A Lineweaver-Burk plot). Each point represents the mean + S.E.M. of 2-3 replicates.
• MIP myo-inositol-1 -phosphate
• VPA valproic acid.
• FIG. 4 illustrates the effect of valproic acid (VPA), valpromide (VPD) and M-TMCD on spreading of rat neuron DRGs.
• VPA valproic acid
• VPD valpromide
• M-TMCD M-TMCD
• Histograms show frequency distribution of the area of the growth cones.
• Units of the Y-axis are %
• Units of the X-axis are ⁇ m of the spread area
• Gray bars contracted growth cones (spread area ⁇ 50 micro m 2 ).
• the present invention discloses the use of 2,2,3,3- tetramethylcyclopropane carboxylic acid derivative compounds (compounds of formula I) for treating a psychiatric disorder preferably a bipolar disorder.
• the present invention provides use of a compound of formula I
• Ri and R 2 are the same or different and are independently selected from hydrogen and C ⁇ -C 6 alkyl group, for the preparation of a medicament for treating a psychiatric disorder.
• treating includes prophylactic and/or therapeutic uses and refers to abrogating, preventing, alleviating, slowing or reversing the progression of a disease or disorder, or substantially preventing the appearance of clinical symptoms of a disease or disorder.
• terapéuticaally effective amount refers to an amount of a compound sufficient to bring about at least one of the effects defined under the term treating.
• the present invention additionally provides a method for treating a psychiatric disorder in a mammal comprising administering to the mammal, a therapeutically effective amount of a compound of formula I
• Ri and R 2 are the same or different and are independently selected from hydrogen and C C 6 alkyl group.
• Rj or R 2 is -C ⁇ alkyl group and the other is hydrogen.
• R is independently selected from a C ⁇ -C 6 alkyl group and hydrogen.
• the C ⁇ -C 6 alkyl group is a -C 4 alkyl group and most preferably the C C 6 alkyl group is a methyl group.
• M-TMCD N-methyl-2,2,3,3-tetramethylcyclopropanecarboxamide
• the C r C 6 alkyl group may be a straight or a branched alkyl group.
• the -C alkyl group may be a straight or a branched alkyl group.
• the psychiatric disorder is a bipolar disorder.
• the compounds of the present invention have a parallel effect to mood stabilizers and are therefore expected to be useful for treating both the manic and depression phases of bipolar disorders.
• the mammal may be a human.
• the compound of formula I is administered as a pharmaceutical composition comprising a compound of formula I and a pharmaceutical acceptable carrier.
• pharmaceutically acceptable carrier refers to an inert non-toxic carrier or diluent that does not cause significant irritation to a subject (mammal) and does not abrogate the biological activity and properties of the administered compound (active ingredient).
• the term "pharmaceutical acceptable carrier” encompasses any of the standard pharmaceutical accepted carriers such as lactose, sodium chloride, glucose, starch, calcium carbonate, kaolin, cellulose, lower alkyl ethers of cellulose, stearic acid, aluminum silicate, polyethylene glycols, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi- synthesized glycerides, water, alcohols, oils, fatty acids, liquid preparations, emulsion preparations and suspension preparations.
• the standard pharmaceutical accepted carriers such as lactose, sodium chloride, glucose, starch, calcium carbonate, kaolin, cellulose, lower alkyl ethers of cellulose, stearic acid, aluminum silicate, polyethylene glycols, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi- synthesized glycerides, water, alcohols, oils, fatty acids, liquid preparations, emulsion preparations and suspension preparations.
• the “pharmaceutical acceptable carrier” may include any sustained release material known in the art such as polymers or waxes.
• excipients such as binders, disintegrants, adsorbents, lubricants, wetting agents, buffering agents, isotonic agents, surface active agents, suspending agents and polymers may be added to the pharmaceutical compositions.
• coloring agents, preservatives, flavoring agents, sweetening a gents a nd o ther i ngridients may b e a dded t o t he p harmaceutical compositions.
• the pharmaceutical acceptable carrier may be a solid, a semi-solid, or a liquid material.
• the pharmaceutically acceptable carrier selected depends on the final form of the composition.
• the final form of the pharmacetical composition may be for example a liquid, an emulsion, a suspension, a solution, a syrup, an elixir, drops, a spray, a cream, an ointment, a lotion, a gel, a paste, an inhalant, a powder, a granule, a tablet, a caplet, a pill, a capsule, a lozenge, a pastille, a suppository, a transdermal patch or an injection.
• the route of administration may be for example, oral, parenteral, topical, transdermal, rectal or buccal administration.
• the route of administration is oral or parenteral such as intravenous, intramuscular, intraperitoneal or subcutaneous and most preferably the route of administration is oral.
• Compositions for administration by the oral route in the form of for example tablets or capsules, are preferred.
• compositions for oral use such as tablets and capsules where the typical solid carrier is an inert substance such as lactose, starch, glucose, methyl cellulose, magnesium sterate, dicalcium phosphate, mannitol and the like, may be prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (for example polyvinylpyrrolidone or hydroxypropyl m ethylcellulose); lubricants (for example magnesium stearate, talc or silica); disintegrants (for example sodium starch glycollate); or wetting agents (for example sodium lauryl sulphate). Tablets may be coated by methods well known in the art.
• binding agents for example polyvinylpyrrolidone or hydroxypropyl m ethylcellulose
• lubricants for example magnesium stearate, talc or silica
• disintegrants for example sodium starch glycollate
• wetting agents for example sodium lauryl sulphate
• Liquid preparations for oral administration may take the form of, for example, solutions, syrups elixirs, emulsions or suspensions.
• a c ompound o f formula I may b e combined with any oral, pharmaceutically acceptable carrier such as ethanol, glycerol, water and the like, or a mixture thereof.
• liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (for example cellulose derivatives or hydrogenated edible fats); emulsifying agents (for example lecithin or acacia); non-aqueous vehicles (for example almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (for example methyl or propyl-p-hydroxybenzoates).
• suspending agents for example cellulose derivatives or hydrogenated edible fats
• emulsifying agents for example lecithin or acacia
• non-aqueous vehicles for example almond oil, oily esters, ethyl alcohol or fractionated vegetable oils
• preservatives for example methyl or propyl-p-hydroxybenzoates.
• the preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
• compositions may be in the form of a suspension, a solution or an emulsion in oily or aqueous vehicles, and may contain pharmaceutically acceptable additives such as suspending agents, emulsifying agents or dispersing agents.
• Pharmaceutical compositions of the invention for rectal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with a suitable carrier comprising for example, cocoa butter, polyethylene glycol or semi-synthesized glycerides.
• Transdermal patches have the added advantage of providing controlled delivery of the compound to the body.
• the transdermal compositions may be prepared by dissolving or dispersing the compound in a proper carrier (a liquid, a semi-solid or a solid carrier).
• the flux rate of the compound can be controlled by either providing a rate controlling membrane or dispersing the active compound in a polymer matrix or gel.
• compositions of the invention for buccal administration are adapted for retention in the mouth rather than swallowing, and consequent release the active component in the buccal cavity.
• Buccal compositions may be in the form of tablets, lozenges or pastilles. Most usually, the composition will be chewed or sucked to lead to the release of the active compound in the mouth. It is also possible to use tablets, for example in the form of a disc of polymeric material, which are attached to the wall of the buccal cavity and which gradually release the compound without being sucked.
• compositions for buccal administration may include carriers such as sucrose, mannitol, sorbitol, acacia, tragacanth, gelatin, glycerin, lactose, calcium carbonate or magnesium phosphate.
• Lozenges usually include the active compound in a flavoured base such as sucrose and acacia or tragacanth.
• Pastilles may include the compound in an inert base such as gelatin and glycerin or sucrose and acacia.
• Adhering agents with low speed of dissolution such as methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxy methyl cellulose or copolymers of methacrylic - and acrylic acid may be used in the preparation o f buccal compositions. Additional excipients may b e added, for example: binding agents such as polyvinyl pyrrolidone, sweetening agents such as calcium saccharinate, lubricating agent such as magnesium stearate, flavouring agents such as maltol, or vanillin.
• binding agents such as polyvinyl pyrrolidone
• sweetening agents such as calcium saccharinate
• lubricating agent such as magnesium stearate
• flavouring agents such as maltol, or vanillin.
• compositions of the invention may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences, 16' ed., Mack Publishing Company, Easton, Pennsylvania. (1980).
• the amount of the compound incorporated in the pharmaceutical composition may vary widely. Factors considered when determining the precise amount are well known to those skilled in the art. Examples of such factors include, but are not limited to, age, sex and weight of the subject being treated, severity of the disease, the dosage form, route of administration being employed and the frequency with which the composition is to be administered.
• the therapeutically effective amount of the compound is in the range of from about 1 mg to about 1000 mg per day (preferably administered orally) and most preferably the therapeutically effective amount is in the range of from about 20 mg to about 500 mg per day.
• the therapeutically effective amount of the compound may be several times greater than for parenteral administration.
• the daily dose may be administered either singly or in multiple dosage over 24-hour period.
• the compounds of formula I can be combined with other anti psychiatric medicaments.
• the present invention additionally provides a pharmaceutical composition for treating a psychiatric disorder (preferably a bipolar disorder) comprising a pharmaceutically acceptable carrier and as an active ingredient a therapeutically e ffective amount o f a c ompound o f formula l as described in the present invention.
• a psychiatric disorder preferably a bipolar disorder
• a pharmaceutically acceptable carrier and as an active ingredient a therapeutically e ffective amount o f a c ompound o f formula l as described in the present invention.
• the term "inhibiting an enzyme having MIP synthase activity” or “ihibitor of MIP synthase” can be used to describe the effect of a compound on an enzymatic activity.
• the term “inhibiting” as it applies to the analysis of enzymatic activity encompasses a range of effects, from completely inhibiting to partially inhibiting.
• the term “inhibiting” can be applied to both in vitro as well as in vivo systems. An example of an assay for determining inhibition is provided in example 2.
• the present invention further provides use of a compound of formula I
• Ri and R 2 are the same or different and are independently selected from hydrogen and C ⁇ -C 6 alkyl group, for the preparation of an inhibitor of MIP synthase.
• Ri or R 2 is C ⁇ -C 6 alkyl group and the other is hydrogen.
• the - alkyl group is a -C 4 alkyl group and most preferably the Ci-C 6 alkyl group is a methyl group.
• the C ⁇ -C 6 alkyl group may be a straight or a branched alkyl group.
• the C 1 -C 4 alkyl group may be a straight or a branched alkyl group.
• M-TMCD N-methyl-2,2,3,3-tetramethylcyclopropanecarboxamide
• R is independently selected from a Ci-C 6 alkyl group and hydrogen.
• the MIP synthase is a mammalian MIP synthase.
• the MIP synthase is a mammalian brain MIP synthase.
• the mammalian MIP synthase is a human MIP synthase.
• mammalian brain MIP synthase is human brain MIP synthase.
• the term "effective amount” refers to an amount which inhibits MIP synthase in a manner which is statistically significant compared to control.
• Ri and R 2 are the same or different and are independently selected from hydrogen and Ci-C 6 alkyl group.
• Ri or R 2 is C C 6 alkyl group and the other is hydrogen.
• the C ⁇ -C 6 alkyl group is a C 1 -C 4 alkyl group and most preferably the Ci-C 6 alkyl group is a methyl group.
• the Ci-C 6 alkyl group may be a straight or a branched alkyl group.
• the Ci-C 4 alkyl group may be a straight or a branched alkyl group.
• M-TMCD N-methyl-2,2,3 ,3 -tetramethylcyclopropanecarboxamide
• the MIP synthase is a mammalian MIP synthase.
• the MIP synthase is a mammalian brain MIP synthase.
• the mammalian MIP synthase is a human MIP synthase.
• the mammalian brain MIP synthase is human brain MIP synthase.
• the MIP synthase is present in a body of a mammal and the effective amount is a therapeutically effective amount.
• M-TMCD N -methyl- 2,2,3,3-tetramethylcyclopropanecarboxamide
• VPD Valpromide
• M-TMCD is highly advantageous for treating bipolar disorders because of its high potency, and due to previous studies which have shown a wider safety of margin and lack of teratogenicity [U.S. pat No. 5,880,157; Isoherranen N. et al. Anticonvulsant profile and teratogenicity of N-methyl- tetramethylcyclopropyl carboxamide; A new antiepileptic drag. Epilepsia 2002; 43:115 - 126]. M-TMCD is additionally advantageous due to its potential lack of hepatotoxicity. Therefore it can be given to women of childbearing age and children.
• the compounds of formula I of the present invention can be prepared according to the methods and procedures described in Sterling et al. (U.S. patent No. 5,880,157), or variations thereof which will be apparent to those skilled in the art.
• M-TMCD was prepared according to the method disclosed in Sterling et al.
• M-TMCD anti-bipolar effect
• MIP synthase model is acceptable for examining bipolar disorders and developing antibipolar drags [Agam G, Shamir A, Shaltiel G, Greenberg ML. Myo-inositol-1 -phosphate (MIP) synthase: a possible new target for antibipolar drags. Bipolar Disorder. 2002;4 Suppl 1 :15-20].
• IP intraperitonealy
• VPA IP twice daily for 9 or 28 days resulted in blood VPA levels of 0.27 ⁇ 0.02 mM
• the mood-stabilizing agents lithium and valproate robustly increase the levels of the neuroprotective protein bcl-2 in the CNS. J Neurochem 1999;72(2):879-82] which approximate therapeutically-relevant plasma 1 evels.
• VPA in drinking water 32.5 ⁇ 2.0 30.1 ⁇ 1.7
• Results are means ⁇ S.E.M.
• Intracellular free inositol is supplied from three sources: specific uptake of rayo-inositol originating in the diet; recycling of the inositol moiety from phosphoinositides by IMPase and de-novo synthesis from glucose-6-phosphate to form inositol- 1 -phosphate by MIP synthase and then dephosphorylation by IMPase [Fisher SK, Novak JE, Agranoff BW. Inositol and higher inositol phosphates in neural tissues: homeostasis, metabolism and functional significance. J Neurochem 2002;82(4):736-54].
• VPA reduces the concentration of yo-inositol, but without a build-up o f i nositol- 1 -phosphate.
• T his s uggested t hat V PA may a lter i nositol synthesis rather than recycling it [Vaden DL, Ding D, Peterson B, Greenberg ML. Lithium and valproate decrease inositol mass and increase expression of the yeast INOl and IN02 genes for inositol biosynthesis. J Biol Chem 2001;276(18):15466-71]. Indeed, we now show in the present invention that human brain MIP synthase activity is inhibitable by therapeutically- relevant VPA concentrations.
• VPA in contrast with lithium, has been shown to have no effect on IMPase activity [Vadnal R, Parthasarathy R. Myo-inositol monophosphatase: diverse effects of lithium, carbamazepine, and valproate. Neuropsychopharmacology 1995;12(4):277-85], it is most probable that the acute in-vivo reduction of inositol levels following VPA treatment is a result of the direct inhibition of MIP synthase activity.
• Table 2 details the drugs and their concentrations compared with their therapeutic concentrations, studied for possible inhibition of human brain MIP synthase activity. Each drag was tested twice, each experiment in triplicate.
• Tricyclic Chlomipramine 200-500 750 (2.63) antidepressants Imipramine 50-350 500 (1.57)
• Rat neuron DRG (dorsal root ganglia) explants.
• DRGs were dissected from the spinal cord area of newborn Sprague Dawley rats and cultured individually on poly-ornithine and laminin coated coverslips in seram-free medium supplemented with mouse 7S form nerve growth factor (NGF-7s, 25 ng/ml) at 37°C with 5% C0 2 .
• NGF-7s mouse 7S form nerve growth factor
• cytosine ⁇ - arabinofuranoside (ara-C, 10 ⁇ M) was added for 24 hours to kill non-neuronal cells.
• VPA, VPD and M-TMCD (1 mM) in fresh seram-free medium were then added to the DRG explants for 24 hour exposure.
• the explants were then fixed in 4% paraformaldehyde in PBS (Phosphate buffered saline) for 20 minutes at room temperature. Growth cones were analysed on an inverted microscope (Zeiss Axiovert) and measured using an NIH Image software.
• VPA inhibits MIP synthase activity in human brain crude homogenate
• the Km of MIP synthase for glucose-6-phosphate and the Vmax derived from the figure are 0.625 mM and 0.02 nmoles/min X mg protein, respectively.
• the Km in the presence of 0.525 mM VPA does not change and the Vmax decreases to 0.006 nmoles/min X mg protein.
• Km and Vmax are Michaelis Menten constants. See Christopher K. Mathews and K.E. Van Holde. Biochemistry. The Benjamin/cummings Publishing Company, Inc. 1990 (357-362).
• VPD and M-TMCD correlates with their effect on rat neurons
• n 10 (control), 10 (VPA), 3 (VPD), 2 (M-TMCD)
• Glucose-6-phosphate is the substrate of MIP synthase.
• O'Donnell et al. [O'Donnell T, Rotzinger S, Nakashima TT, Hanstock CC, Ulrich M, Silverstone PH. Chronic lithium and sodium valproate both decrease the concentration of myo-inositol and increase the concentration of inositol monophosphates in rat brain.
• Brain Res 2000;880(l-2):84-91] measured a basal glucose-6-phosphate concentration of 0.226 ⁇ mol/g in rat brain. Assuming similar brain glucose-6-phosphate levels in human and rat, in-vivo MIP synthase activity is below half of its Vmax in the human brain, enabling a significant range for regulatory manipulation.
• VPD and M-TMCD the inhibitory effect VPD and M-TMCD on human brain MIP synthase activity also correlates with their effect on the growth cones of rat DRGs.
• M-TMCD is preferred compared to VPA and VPD for treating bipolar disorders because of its high potency and due to previous studies which have shown wider safety of margin and lack of teratogenicity [U.S. pat No. 5,880,157; Isoherranen N. et al. Anticonvulsant profile and teratogenicity of N-methyl-tetramethylcyclopropyl carboxamide; A new antiepileptic drag. Epilepsia 2002; 43:115 - 126].
• M- TMCD is additionally advantageous due to its potential lack of hepatotoxicity. Therefore it can be given to women of childbearing age and children.

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