the term &# 34 ; agonist &# 34 ; as used herein means any compound which increases the flow of cations through the kainate receptor , that is , works as a channel opener , and which has not been observed to decrease the flow of cations through the same receptor . the term &# 34 ; antagonist &# 34 ; as used herein means any compound which reduces the flow of cations through the kainate receptor , that is , works as a channel closer , and which has not been observed to increase the flow of cations through the same receptor . the term &# 34 ; partial agonist &# 34 ; as used herein means a compound which modulates an eaa receptor so as to increase or decrease the flux of cations through the ligand - gated channel depending on the presence or absence of the principal site modulator ( s ). in the absence of the principal site modulator ( s ), a partial agonist increases the flow of cations through the ligand - gated channel but at a lower flux than achieved by the principal site modulator ( s ). a partial agonist partially opens the receptor channel . in the presence of the principal site modulator ( s ), a partial agonist decreases the flow of cations through the ligand - gated channel below the flux normally achieved by the principal site modulator ( s ). the term &# 34 ; principal site ligand &# 34 ; as used herein refers to known endogenous ligands binding to a site . the term &# 34 ; glutamic acid &# 34 ; as used herein means the amino acid l - glutamic acid (&# 34 ; glu &# 34 ;). the term &# 34 ; neuropsychopharmacological disorder &# 34 ; as used herein means a disorder resulting from , or associated with , a reduced or excessive flux of ions through the ka receptor ligand - gated cation channel , and includes cognitive , learning , and memory deficits , chemical toxicity ( including substance tolerance and addiction ), excitotoxicity , neurodegenerative disorder ( such as huntington &# 39 ; s disease , parkinson &# 39 ; s disease , and alzheimer &# 39 ; s disease ), post - stroke sequelae , epilepsy , seizures , mood disorders ( such as bipolar disorder , dysthymia , and seasonal affective disorder ), and depression . neurodegenerative disorders can result from dysfunction or malfunction of the receptor . as used herein , this term includes pain . the term &# 34 ; nmda receptor &# 34 ; as used herein means a postsynaptic receptor which is stimulated , at a minimum , by the eaa glutamic acid as well as by nmda , but is not stimulated by ampa or kainic acid . it is a ligand - gated receptor . the term &# 34 ; ampa receptor &# 34 ; as used herein means a postsynaptic receptor which is stimulated by the eaas glutamic acid as well as by ampa , but is not stimulated by nmda and only minimally and at high concentrations by kainic acid . it is a ligand - gated receptor . the term &# 34 ; ka receptor &# 34 ; as used herein means a postsynaptic receptor which is stimulated , at a minimum , by the eaa glutamic acid as well as by ka , but is not stimulated by nmda and only minimally and at high concentrations by ampa . it is a ligand - gated receptor . the term &# 34 ; potency &# 34 ; as used herein refers to the molar concentration at which a specified effect on a receptor channel is observed . specifically , potency for a compound exhibiting antagonistic effect is presented as the ic 50 value , which is the concentration at which inhibition of channel opening is 50 % of the maximum inhibition achievable . lower values indicate higher potency . potency for a compound exhibiting agonistic effect is presented as the ec 50 value , which is the concentration at which enhancement of channel opening is 50 % that of the maximum enhancement achievable . lower values indicate higher potency . the term &# 34 ; efficacious &# 34 ; as used herein refers to a comparison of the maximum channel opening or closing achieved by a particular compound with maximum channel opening or closing achieved by a principal site ligand . efficacy refers to magnitude of a specified effect . the term &# 34 ; pharmacophore &# 34 ; as used herein means an atom or group of atoms that electrostatically or through hydrogen bonds interacts directly with the receptor protein . the term &# 34 ; specifically binds &# 34 ; as used herein means a compound binding to a receptor with an affinity at least three times as great as a compound which binds to multiple sites or receptors . when an alkyl substituent is identified herein , the normal alkyl structure is intended ( i . e . butyl is n - butyl ) unless otherwise specified . however , when radicals are identified ( e . g . r 1 ), both branched and straight chains are included in the definition of alkyl , alkenyl , and alkynyl . pharmaceutically acceptable salts include both the metallic ( inorganic ) salts and organic salts ; a list of which is given in remington &# 39 ; s pharmaceutical sciences 17th edition , p . 1418 ( 1985 ). it is well known to one skilled in the art that an appropriate salt form is chosen based on physical and chemical stability , flowability , hydroscopicity and solubility . depending on the required activity , compounds from this class may be used as pharmaceutical neuroprotectants to treat acute cases of cns injury and trauma as well as to treat convulsions , mood disorders , alleviation of pain , and other neuropsychiatric and neurodegenerative diseases due , in part , to chronic disturbances in the control of the ion flux through the ka receptor . similarly , the compounds of this class can be selected for the required activity to treat the disorder . as used herein , the common definitions of neuropsychiatric and neurogenerative disorders are intended , where diagnosis is based on the alleviation of abnormal behavior , rather than histopathology . a class of alkyl carboxy amino acid compounds has been discovered which bind to the ka receptor and modulate the ka receptor function . these compounds have the following formula : ## str2 ## wherein : r 1 is r 2 and r 3 taken together can be -- ch 2 ( ch 2 ) p ch 2 --; r 2 and r 3 taken together can be -- ch 2 ( ch 2 ) p ch 2 --; more preferred of the preferred compounds are compounds of formula i which selectively bind to the kainate receptor wherein : the compounds of formula i my be prepared using the reactions and techniques described in this section . the reactions are performed in solvents suitable to the reagents and materials employed and suitable for the transformation being effected . it is understood by those skilled in the art of organic synthesis that the functionality present on the molecule must be consistent with the chemical transformations proposed . this will frequently necessitate judgment as to the order of synthetic steps , protecting groups required , deprotection conditions and generation of enolate ions to enable attachment of appropriate groups on the molecule . ## str3 ## in scheme i , ( s )- or ( r )- glutamic acid is esterified under standard conditions ( march , &# 34 ; advanced organic chemistry &# 34 ;, 4th edition 1992 , wiley - interscience publication , new york ) with an appropriate alcohol , such as methanol , ethanol , t - butanol or benzyl alcohol . the amine group of the diester product , formula ii , is then protected under standard conditions , buehler and pearson , &# 34 ; survey of organic synthesis &# 34 ;, 1970 , wiley - interscience publication , new york , by an appropriate amine protecting group , such as an aromatic amide such as nitrobenzoyl , naphthoyl , n - tert - butoxycarbonyl ( boc ) or carbobenzyloxy ( cbz ). the enolate of this fully protected glutamic acid , iii , is prepared by reacting iii with a strong base , such as lithium bis ( trimethylsilyl ) amide or lithium diisopropylamide , in an inert solvent , such as tetrahydrofuran or ethyl ether , at a temperature range of - 78 ° to 0 ° c . for 1 to 5 hr . the enolate is then reacted with an electrophile such as an alkylhalide , at a temperature between - 78 ° to - 30 ° c . for 0 . 5 to 24 hr to afford compounds of formula iv . if the starting glutamic acid has the ( 2s ) stereochemistry , the product has the ( 2s , 4s ) stereochemistry . conversely if the starting glutamic acid has the ( 2r ) stereochemistry , the product has the ( 2r , 4r ) stereochemistry . the compounds described herein wherein r 1 are alkyl , alkenyl , alkynyl , and cycloalkyl are prepared from this procedure . the compound of formula v is prepared by reacting the compound of formula iv with a strong aqueous acid such as hcl at a temperature of 0 ° c . to reflux for 1 to 48 hr or by treatment with lioh in a solvent such as thf or ethanol at a temperature of 0 ° c . to 60 ° c . for 0 . 5 to 18 hr , then treatment with trifluoracetic acid in a solvent such as methylene chloride ( ch 2 cl 2 ) at room temperature for 0 . 5 to 24 hr . ## str4 ## the compounds of formulas ix , x , xi and xii can be prepared according to scheme ii . compounds of formula ix , which are a diastereomeric mixture , can be prepared by the procedure described in &# 34 ; chemistry of amino acids &# 34 ;, ed . j . p . greensein and m . winitz , vol . 3 , 1984 ; kreiger publishing : malabar , fla ., pp . 2438 - 2445 and references cited therein . the racemic diacid compounds of formula x ( 2s , 4r ) and ( 2r , 4s ), obtained by fractional crystallization , can then be separated into the individual stereoisomers by standard physical or chemical procedures as described in march , &# 34 ; advanced organic chemistry &# 34 ;, 4th edition 1992 , wiley - interscience publication , new york , and references cited therein . as an example , the compounds of formula x can be esterified under the standard conditions described above and then the amine acylated with a chiral acylating agent , such as ( r )-(+)- or ( s )-(-)- α - methoxy - α -( trifluoromethyl ) phenylacetyl chloride in an inert solvent , such as ch 2 cl 2 , with an amine base present , such as triethylamine , pyridine or n , n - dimethylamino - pyridine , at a temperature of 0 ° c . to reflux of the solvent for 0 . 5 to 24 hr . the resulting diastereomers can then be physically separated by fractional crystallization or chromatography and then the protected chiral isomers can be deprotected by reacting with a strong aqueous acid such as hcl at a temperature of 0 ° c . to reflux for 1 to 48 hr . to give individual isomers such as the compounds of formulas xi or xii . alternatively xi and xii can be prepared by the procedures outlined in scheme iii . the intermediate xiv can be prepared by the procedures described by woo and jones ( tel . lett . 32 ( 47 ), 6949 - 6952 , 1991 ). pyroglutamic acid can be esterified under standard conditions ( march , &# 34 ; advanced organic chemistry &# 34 ;, 4th edition 1992 , wiley - interscience publication , new york ) with an appropriate alcohol , such as methanol , ethanol , t - butanol or benzyl alcohol to give xiii . the ester xiii is then reduced with a reducing agent such as nabh 4 in an alcohol solvent such as ethanol (&# 34 ; etoh &# 34 ;) at 0 ° c . to room temperature for 1 to 24 hr . the corresponding alcohol is then silylated with a reagent such as ( t - bu ) ph 2 sicl in an inert solvent such as thf or methylene chloride at 0 ° c . to room temperature for 1 to 24 hr . the amide is then protected with an amino acid protecting group such as boc by treatment with boccl or ( boc ) 2 o and a base such as pyridine or et 3 n in an inert solvent such as ch 2 cl 2 at - 10 ° c . to room temperature for 1 to 6 hr . the enolate of xiv is prepared by reacting xiv with a strong base , such as lithium bis ( trimethylsilyl ) amide or lithium diisopropylamide , in an inert solvent , such as tetrahydrofuran or ethyl ether , at a temperature range of - 78 ° to 0 ° c . for 1 to 5 hr . the enolate is then reacted with an electrophile such as an alkylhalide , at a temperature between - 78 ° to 30 ° c . for 0 . 5 to 24 hr to afford compounds of formula xv . xv is then converted to the acid xvi by first deprotecting the alcohol by treatment with f in an inert solvent such as thf at room temperature then the alcohol is oxidized with an oxidizing agent such as rucl 3 / naio 4 . ## str5 ## the compounds of formula xvii can be prepared by acylation of the appopriately protected amino acid as described in scheme iv , part a . the amino acid can be treated with an acylating agent , such as an acyl halide or an anhydride , in an inert solvent such as toluene or ch 2 cl 2 with a base , such as pyridine or n , n - dimethylaminopyridine or in a mixed solvent system such as toluene / water with a base such as naoh or na 2 co 3 at a temperature of 0 ° c . to reflux of the solvent . deprotection of the product under the appropriate conditions would give xvii . the compounds of formula xviii can be prepared by formylation of the appropriately protected amino acid as described in scheme iv , part b . the amino acid can be treated with a formylating agent , such as a mixed anhydride , in an inert solvent such as toluene or ch 2 cl 2 with a base , such as pyridine or n , n - dimethylaminopyridine or in a mixed solvent system such as toluene / water with a base such as naoh or na 2 co 3 at a temperature of 0 ° c . to reflux of the solvent . deprotection of the product under the appropriate conditions would give xviii . the compounds of formula xix and xx can be prepared by alkylation of the appropriately protected amino acid as described in scheme iv , part c . the amino acid can be reductively mono - or bis - alkylated by treatment with the desired aldehyde such as acetaldehyde and a reducing agent such as nabh 3 cn in a solvent such as acetic acid at a temperature of between 20 ° c . and 80 ° c . deprotection of the product under the appropriate conditions would give xix and xx . ## str6 ## the compounds of formula i where y is heterocyclic can be prepared by modifications known to one skilled in the art of the procedures described in epa 590 , 789 by eli lilly and the references therein . the compounds described herein and their preparation will be understood further from the following non - limiting examples . in these examples , unless otherwise indicated , all temperatures are in degrees celsius and parts and percentages are by weight . a variety of analogs of glutamic acid were synthesized , in particular , analogs of 4 - alkyl - substituted glutamate . 4 - methylglutamate has two chiral centers , resulting in four stereoisomers , as synthesized and isolated below . to a solution of 14 . 7 g ( 100 mmol ) of d - glutamic acid in 150 ml of ethanol cooled to 0 ° c ., 11 ml ( 150 mmol ) of thionyl chloride was added dropwise . the mixture was then heated until it became clear . the reaction mixture was then allowed to stir at room temperature for 48 hr . after evaporating the solvent , a clear oily residue was obtained which was carried on to the next step . the oily residue and 18 . 5 g ( 100 mmol ) of 4 - nitrobenzoyl chloride was stirred in 150 ml of methylene chloride and 20 ml of water . a 100 ml of 20 % na 2 co 3 solution was slowly added . the reaction mixture was allowed to stir at room temperature for 3 hr . the organic phase was separated and after evaporating the solvent , the residue was crystallized from diethyl ether . m . p . 90 °- 92 ° c . ; 1 h - nmr ( 200 mhz , cdcl 3 ): δ 1 . 25 ( t , j = 7 . 2 hz , 3h ), 1 . 30 ( t , j = 7 . 2 hz , 3h ), 2 . 25 ( m , 2h ); 2 . 50 ( m , 2h ); 4 . 12 ( q , j = 7 . 1 hz , 2h ); 4 . 22 ( q , j = 7 . 1 hz , 2h ); 7 . 5 ( d , j = 7 . 1 hz ), 8 . 00 ( dd , j = 2 . 0 , 6 . 9 hz , 2h ); 8 . 30 ( dd , j = 1 . 9 , 6 . 9 hz , 2h ). to a solution of 3 . 52 g ( 10 mmol ) of n -( 4 - nitrobenzoyl )- d - glutamic acid diethyl ester in 100 ml of anhydrous tetrahydrofuran which was cooled to - 78 ° c . under nitrogen , 22 ml ( 22 mmol ) of 1 . 0m solution of lithium bis ( trimethylsilyl ) amide in thf was slowly added via syringe . the mixture was stirred at - 78 ° c . for 1 hr , then 40 mmol of iodomethane was added . the reaction mixture was then quenched with saturated ammonium chloride . after evaporating half of the solvent , the mixture was diluted with 200 ml of water and extracted with methylene chloride ( 3 x 50 ml ). the combined extracts were washed with water , brine , and dried over mgso 4 . the solvent was evaporated and the oily residue purified through a column of silica gel , eluting with a mixture of ethyl acetate and hexanes ( 1 : 1 ) to yield 1 . 6 g of oil . 1 h - nmr ( 200 mhz , cdcl 3 ): δ 1 . 25 ( m , 9h ), 2 . 12 ( m , 2h ), 2 . 6 ( m , 1h ), 4 . 2 ( m , 4h ), 4 . 80 ( m , 1h ), 6 . 95 ( d , j = 7 . 8 hz , 1h ), 8 . 0 ( d , j = 8 . 0 hz , 2h ), 8 . 3 ( d , j = 8 . 0 hz , 2h ). the product b above was refluxed in 50 ml of 6n hcl for 2 hr . and then cooled to room temperature . the precipitate was filtered and the filtrate was concentrated in vacuo . the residue was dissolved in 50 ml of distilled water and washed with 50 ml of 5 % of trioctylamine in chloroform twice . the aqueous phase was concentrated in vacuo and the oily residue crystallized in acetone and water . m . p . 190 °- 192 ° c . ; 1 h - nmr ( 200 mhz , d 2 o ): δ 1 . 24 ( d , j = 7 . 1 hz , 3h ); 2 . 05 ( m , 1h ); 2 . 2 ( m , 1h ), 2 . 80 ( m , 1h ); 4 . 07 ( dd , j = 6 . 3 , 7 . 9 hz , 1h ). using appropriate starting materials , the ( 2s , 4s )- 4 - methyl glutamic acid was obtained by using the procedures described in parts b and c of example 1 . m . p . 179 °- 182 ° c . ; 1 h - nmr ( 200 mhz , d 2 o ): δ 1 . 24 ( d , j = 7 . 1 hz , 3h ); 2 . 05 ( m , 1h ); 2 . 2 ( m , 1h ), 2 . 80 ( m , 1h ); 4 . 07 ( dd , j = 6 . 3 , 7 . 9 hz , 1h ). sodium metal ( 500 mg ) in small pieces was dissolved in 450 ml of absolute ethanol , and to this solution 400 mg of sulfur and 37 g ( 170 mm ) of diethyl acetamidomalonate were added . then 30 g ( 300 mm ) of methyl methacrylate was added dropwise over a 4 hr period while refluxing . the reaction mixture was refluxed for another hour . the solvent was removed by evaporation in vacuo and the residue crystallized from ethanol to afford 33 . 4 g ( 62 %) solid with m . p . 107 °- 109 ° c . 5 g ( 15 . 8 mmol ) of this solid material was refluxed in 20 % hcl for 2 hr then the solvent removed by evaporation in vacuo . the residue was dissolved in 50 ml of distilled water and washed with 5 % of trioctylamine in chcl 3 . the aqueous phase was evaporated in vacuo and the oily residue dissolved in a very small amount of water (˜ 1 ml ) and crystallized with an excess of acetone to afford 1 . 3 g ( 54 %) of the title compound with m . p . 163 °- 164 ° c . ; 1 h - nmr ( 300 mhz , d 2 o ): δ 1 . 17 ( d , j = 7 . 1 hz , 1 . 5h ), 1 . 18 ( d , j = 7 . 1 hz , 3h ), 1 . 83 ( m , 1h ), 1 . 95 ( m , 0 . 5h ), 2 . 1 ( m , 0 . 5h ), 2 . 25 ( m , 0 . 5h ), 2 . 65 ( m , 1h ), 3 . 85 ( dd , j = 6 . 5 , 6 . 7 hz , 1 . 5h ). 13 c - nmr ( 300 mhz , d 2 o ): δ 19 . 7 , 19 . 8 , 36 . 2 , 36 . 4 , 38 . 8 , 38 . 9 , 54 . 7 , 54 . 9 , 175 . 4 , 182 . 5 . ( 2r , 4s ) and ( 2s , 4r )- 4 - methyl glutamic acid were obtained by fractional crystallization in water and acetone at 4 ° c . from racemic diastereomers obtained in example 3 . 1 h - nmr ( 300 mhz , d 2 o ): δ 1 . 18 ( d , j = 7 . 0 hz , 3h ), 1 . 83 ( m , 1h ), 2 . 25 ( m , 1h ), 2 . 65 ( m , 1h ), 3 . 85 ( dd , j = 6 . 5 , 6 . 8 hz , 1h ); 13 c - nmr ( 300 mhz , d 2 o ): δ 19 . 8 , 36 . 3 , 38 . 8 , 55 . 0 , 175 . 6 , 182 . 5 . the title compound was prepared using literature procedures from ( s )-(-)- 2 - pyrrolididone - 5 - carboxylic acid . mp = 108 °- 109 ° c . 1 h nmr ( 200 mhz , cdcl 3 ): δ 7 . 62 ( m , 5h ), 7 . 40 ( m , 5h ), 4 . 20 ( m , 1h ), 3 . 88 ( dd , j = 10 . 4 , 4 . 1 hz , 1h ), 3 . 70 ( dd , j = 10 . 4 , 2 . 5 hz , 1h ), 2 . 80 ( m , 1h ), 2 . 45 ( m , 1h ), 1 . 75 ( m , 1h ), 2 . 10 ( m , 2h ), 1 . 42 ( s , 9h ), 1 . 05 ( s , 9h ). to a solution of ( s )- 1 - t - butoxycarbonyl - 5 - t - butyldiphenylsiloxymethyl - pyrrolidine - 2 - one ( 15 g , 33 mmol ) in thf ( 250 ml ) at - 78 ° c . a 1m solution of lin ( sime 3 ) 2 ( 35 ml , 35 mmol ) was slowly added . after stirring for 1 hr , iodomethane ( 6 . 2 ml , 100 mmol ) was added . the reaction mixture was allowed to stir for another 2 hr at - 78 ° c . and then quenched with acetic acid . the mixture was concentrated into half volume , diluted with water ( 200 ml ) and extracted with ethyl acetate ( etoac ). the combined extracts were washed with water , brine and dried over mgso 4 . the solvent was evaporated in vacuo and the residue purified by flash column chromatography on silica gel , eluted with etoac : hexane ( 1 : 2 . 5 ). the desired ( 2s , 5r ) isomer was eluted first from the column and crystallized in hexanes to give 7 . 3 g ( 47 %) of product as white crystals . mp = 84 °- 85 ° c . 1 h nmr ( 200 mhz , cdcl 3 ): δ 7 . 62 ( m , 5h ), 7 . 40 ( m , 5h ), 4 . 12 ( m , 1h ), 3 . 85 ( dd , j = 10 . 3 , 4 . 7 hz , 1h ), 3 . 72 ( dd , j = 10 . 3 , 2 . 8 hz , 1h ), 2 . 82 ( m , 1h ), 2 . 31 ( dd , j = 12 . 7 , 8 . 9 hz , 1h ), 1 . 75 ( m , 1h ), 1 . 42 ( s , 9h ), 1 . 20 ( d , j = 7 . 0 hz , 3h ), 1 . 02 ( s , 9h ). to a solution of ( 3r , 5s )- 1 - t - butoxycarbonyl - 5 - t - butyldiphenylsiloxymethyl - 3 - methyl - pyrrolidine - 2 - one ( 17 . 8 g , 38 . 1 mmol ) and glacial acetic acid ( 2 eq ) in dry thf ( 50 ml ) at 0 ° c . was added a 1 . 0m solution of tetrabutylammonium fluoride in thf ( 150 ml , 150 mmol ). the solution was allowed to warm room temperature and stir overnight . ethyl acetate ( 500 ml ) was added and the organic phase extracted with aqueous ammonium chloride ( 20 %, 3 x 200 ml ). the combined aqueous phases were extracted with ethyl acetate ( 200 ml ). the combined organic phases were washed with brine ( 500 ml ), dried over na 2 so 4 , filtered and evaporated to dryness . the crude product was purified by filtration through silica gel , eluted with 70 % etoac in hexane to give the product as a clear oil , which was carried on for next step without further characterization . to a solution of ( 3r , 5s )- 1 - t - butoxycarbonyl - 5 - hydroxymethyl - 3 - methylpyrrolidine - 2 - one in a solvent mixture of acetonitrile : carbon tetrachloride : water ( 2 : 2 : 3 , 266 ml ) was added sodium periodate ( 3 eq , 24 . 0 g ) and ruthenium trichloride ( 2 . 2 mol %, 0 . 174 g ). the solution was stirred 2 hr at room temperature and then diluted by the addition of dichloromethane ( 500 ml ) and brine ( 200 ml ). the organic phase was separated and the aqueous phase was extracted with dichloromethane ( 3 x 200 ml ). the combined organic phases were dried over na 2 so 4 then celite added . the solution was filtered under suction through a bed of celite and the filtrate was evaporated to give an oily residue which was crystallized in ethyl acetate and hexane to give 5 . 03 g product ( 54 %). the mother liquor was purified by flash column chromatography on silica gel , eluting with 70 % ethyl acetate in hexane ( with 1 % of formic acid ) to give an additional 1 . 21 g ( 13 %) of the acid ( total 67 % yield in two steps ). 1 h nmr ( 200 mhz , cdcl 3 ): δ 6 . 65 ( br s , 1h ), 4 . 60 ( d , j = 8 . 6 , 0 . 9 hz , 1h ), 2 . 70 ( m , 1h ), 2 . 40 ( dd , j = 12 . 5 , 8 . 8 hz , 1h ), 2 . 0 ( m , 1h ), 1 . 55 ( s , 9h ), 1 . 25 ( d , j = 7 . 0 hz , 3h ). a solution of ( 3r , 5s )- 1 - t - butoxycarbonyl - 5 - carboxy - 3 - methylpyrrolidine - 2 - one ( 6 . 2 g , 25 . 5 mmol ) in thf ( 50 ml ) was treated with lithium hydroxide monohydrate ( 3 eq , 3 . 20 g ) and water ( 5 ml ). after stirring for 16 hr at room temperature the thf was removed in vacuo and water ( 20 ml ) was added . the ph was adjusted to 3 by the addition of glacial acetic acid , ether ( 100 ml ) was added and the layers separated . the aqueous phase was extracted with ether ( 3 x 100 ml ) and the combined organic phases were washed with brine ( 400 ml ), dried over na 2 so4 , filtered and evaporated to dryness , azeotroping with toluene ( 3 x 15 ml ). the residue was dried under high vacuum to give 6 . 58 g of the product ( 99 %) as a white foam which was used without further purification : r f 0 . 8 ( 1 % formic acid in ethyl acetate , developed with ninhydrin ). 1 h nmr ( 200 mhz , d 2 o ): δ 3 . 80 ( dd , j = 10 . 4 , 4 . 7 hz , 1h ), 2 . 45 ( m , 1h ), 2 . 0 ( m , 1h ), 1 . 60 ( ddd , j = 12 . 8 , 4 . 2 , 10 . 3 hz , 1h ), 1 . 25 ( s , 9h ), 1 . 0 ( d , j = 7 . 0 hz , 3h ). the boc - protected diacid , ( 2s , 4r )- n - t - butoxycarbonyl - 4 - methyl glutamic acid , was subjected to a mixture of trifluoroacetic acid : methylene chloride ( 40 : 60 , 100 ml ) for 3 hr at room temperature . the volatiles were removed in vacuo and the residue was azeotroped with toluene ( 50 ml ). water ( 150 ml ) was added and the aqueous phase extracted with a 5 % solution of trioctylamine in chloroform ( 3 x 200 ml ). the combined organic phases were washed with water ( 50 ml ) and the combined aqueous phases evaporated by being placed on a lyophilizer for 48 hr to give the product ( 4 . 6 g , 66 % in two steps ) as a white foam which was recrystallized in acetone and water . mp = 169 °- 170 ° c ., 1 h nmr ( 200 mhz , d 2 o ): δ 3 . 80 ( dd , j = 7 . 3 , 7 . 3 hz , 1h ), 2 . 55 ( m , 1h ), 2 . 15 ( ddd , j = 14 . 7 , 8 . 7 , 6 . 6 hz , 1h ), 1 . 75 ( ddd , j = 14 . 6 , 7 . 4 , 5 . 4 hz , 1h ), 1 . 05 ( d , j = 7 . 0 hz , 3h ). anal . calculated for c 6 h 11 no 4 : c , 44 . 71 ; h , 6 . 88 ; n , 8 . 69 . found : c , 44 . 59 ; h , 6 . 85 ; n , 8 . 61 . examples shown in table 1 were prepared or can be prepared by the methods outline in schemes i - iv presented above and procedures described in the examples using the appropriate starting materials and reagents . ## str7 ## table 1______________________________________exemplary compounds of formula 1 stereoex . r . sup . 1 r . sup . 2 , r . sup . 3 config . anal . ______________________________________1 -- ch . sub . 3 h , h 2r , 4r mp 115 - 118 ° c . 2 -- ch . sub . 3 h , h 2s , 4s , mp 179 - 182 ° c . 3 -- ch . sub . 3 h , -- ch . sub . 3 2r , 4r4 -- ch . sub . 3 h , -- cho 2r , 4r5 -- ch . sub . 3 h , -- coch . sub . 3 2r , 4r6 -- ch . sub . 3 h , h 2s , 4s & amp ; mp 163 - 164 ° c . 2r , 4r & amp ; 2s , 4r & amp ; 2r , 4s7 -- ch . sub . 3 h , h 2r , 4s & amp ; nmr 2s , 4r8 -- ch . sub . 3 h , h 2s , 4r mp 169 - 170 ° c . 9 -- ch . sub . 3 h , h 2r , 4s nmr10 -- ch . sub . 3 -- ch . sub . 3 , h 2r , 4s 2s , 4r11 -- ch . sub . 3 -- ch . sub . 3 , h 2s , 4r12 -- ch . sub . 3 -- ch . sub . 3 , h 2r , 4s______________________________________ models were developed using molecular simulations inc . cerius2 ® 1 . 5 software on a silicon graphics indigo ii workstation . the model was constructed based on the structure of six known agonists of the ka receptor , ka , hfpa , acromelic acids a and b , l - ccg - iii , and l - ccg - iv , and two modulators , shown in example 2 and ( 2s , 4s )- 4 - ethyl glutamic acid , and their respective ic 50 &# 39 ; s for inhibiting 3h ! kainic acid binding , shown in table 2 . individual model agonists were analyzed with all carboxylic acids deprotonated and the basic amine protonated and minimized using the universal forcefield without a coulombic or hydrogen bond contribution to the overall energy . the global minima were aligned using the basic amine n 1 and the carboxyl oxygens o 1 , o 2 , o 3 and o 4 as overlapping pharmacophore constraints , as shown in the pharmacophore model in fig3 . those compounds that did not align satisfactorily on kainic acid constraints were adjusted by deleting the o 2 overlap constraint . table 2__________________________________________________________________________in vitro binding assays at glutamate receptors in rat brain . activity predicted residualstructure ( nm )* ( nm ) ( nm )** e . sub . inside e . sub . interact e . sub . strain logp__________________________________________________________________________hfpa 8 . 22 8 . 11 + 0 . 11 39 . 937 - 104 . 942 62 . 025 - 1 . 320kainic acid 7 . 92 7 . 89 + 0 . 03 38 . 946 - 107 . 775 44 . 499 - 1 . 345acromelic 6 . 93 6 . 93 + 0 . 00 14 . 320 - 119 . 345 68 . 632 - 5 . 650acid bacromelic 6 . 48 6 . 36 + 0 . 12 - 2 . 992 - 115 . 594 56 . 197 - 6 . 35acid al - ccg - iv 5 . 78 6 . 10 - 0 . 316 - 27 . 917 - 98 . 480 20 . 901 - 3 . 290ex . 2 5 . 52 5 . 72 - 0 . 20 - 82 . 725 - 94 . 053 62 . 188 - 2 . 850 ( 2s , 4s )- 4 - 4 . 92 4 . 72 + 0 . 20 - 114 . 021 - 89 . 177 13 . 197 - 2 . 320ethyl glutamicacidl - ccg - iii 4 . 59 4 . 53 + 0 . 06 - 122 . 706 - 63 . 174 29 . 249 - 3 . 290l - glutamic 6 . 52 6 . 70 - 0 . 18 - 5 . 523 - 94 . 286 39 . 678 - 3 . 250acidampa 4 . 00 3 . 93 + 0 . 07 - 57 . 321 1334 . 77 24 . 322 - 2 . 910__________________________________________________________________________ * activity is measured as the actual inhibition of 3h ! kainic acid binding to the kainate receptor , - log ( ic . sub . 50 kainate binding ). ** residual is measured as the difference between the actual and predicted binding to the kainate receptor . a pseudo - receptor surface was constructed from the four most potent agonists ( hfpa , ka , and acromelic acid a and b ) and four less potent compounds ( example 2 , ( 2s , 4s )- 4 - ethyl glutamic acid , l - ccgiii and l - ccgiv ). a pseudo - receptor surface is formed as the hypothetical outer van der waals radii from one or a series of molecules that describes the combined three - dimensional properties of the molecule or molecules . this method constructs the pseudo - receptor surface based on the structure of each of the eight compounds , weighting the respective contribution of each structure based on the relative binding affinities of the agonists ( expressed as - log ( ic 50 ) for inhibiting 3 h ! kainic acid binding )). the surface fit to the chosen compounds was allowed to vary from the combined van der waals radii , to this distance plus 0 . 025 nm . the interaction or fit of the eight compounds with the pseudo - receptor surface was evaluated employing all energy terms . the interaction was evaluated in terms of e inside , e relax , e strain and e interact . a qsar table was constructed using the above described terms and a range of other calculated physical properties of the individual molecules , shown in table 2 . a genetic algorithm analysis of this data revealed a good correlation of the binding affinity ( ic 50 ) as described above with e interact , e inside and logp ( partition coefficient ). the equation generated is : two known ka receptor agonists , l - glutamic acid and s - ampa , were evaluated to test the utility of the receptor model and the qsar equation . the model predicted the correct ic 50 values . fig4 is a graph of the log ic 50 predicted 3 h ! kainate versus log ic 50 actual 3 h ! kainate , for the ka agonist model , ampa , and l - glutamate . the same methodologies can be applied to the ampa receptor and other glutamate receptors . iv . pharmaceutical compositions and therapeutic applications based on in vitro and in vivo studies the basic discovery described herein is of a class of compounds that selectively bind at the ka receptor and modulate ka receptor function . binding can be determined using standard techniques , to yield data such as that in table 3 . modulation of the ka eaa receptor , as demonstrated by compounds showing potent in vitro affinity for the ka receptor , make the compounds useful for treating human neuropsychopharmacological conditions related to eaas . since the compounds described herein regulate the in vitro effects of ka , they are useful in the in vivo treatment of eaa dependent psychosis , neurodegeneration , convulsions , pain and learning and memory deficits . the following analytical methods were used to determine the binding for each ligand and are identified by the literature reference where each is more fully set forth : murphy , et al . &# 34 ; binding of 3 h !- 3 -( 2 - carboxypiperazin - 4 - yl - d - propyl - 1 - phosphonic acid ) to rat brain membranes : a selective , high affinity ligand of n - methyl - d - aspartate receptors &# 34 ; j . pharm . exper . therapeutics . 240 : 778 - 784 ( 1987 ). murphy , et al . &# 34 ; characterization of quisqualate recognition sites in rat brain tissue using 3 h ! alpha - amino - 3 - hydroxy - 5 - methylisoxazole - 4 - propionic acid and a filtration assay &# 34 ; neurochemical research . 12 : 775 - 781 ( 1987 ). london , et al . &# 34 ; specific binding of 3 h ! kainic acid to receptor sites in rat brain &# 34 ;. molecular pharmacology . 15 : 492 - 5 - 5 ( 1979 ). the ic 50 values in table 3 were determined according to these procedures by exposing the receptor preparation to a radiolabeled ligand and increasing amounts of test ligand . the amount of radioactivity bound to the receptor preparation will decrease in the presence of test compounds which compete for the binding site for the radiolabeled ligand . table 3______________________________________binding of compounds to glutamate receptorpreparations . nmda . sup . 3 h ! mk - nmda ampa ka 801 ec . sub . 50 cgs - 19755 ic . sub . 50 ic . sub . 50compound r ( μm ) ic . sub . 50 ( μm ) ( μm ) ( μm ) ______________________________________ampa na 5 . 6 -- 0 . 005 2 . g1kainica cid na 34 . 6 & gt ; 100 5 . 1 0 . 011l - glutamate h 0 . 24 0 . 2 0 . 26 0 . 201 ch . sub . 3 26 . 6 10 & gt ; 100 3 . 02 ch . sub . 3 12 . 9 10 13 . 5 3 . 08 ch . sub . 3 36 . 4 7 & gt ; 100 0 . 0357 ch . sub . 3 130 75 10 1 . 34______________________________________ it can be seen from the data in table 3 that the compounds described herein specifically bind to the kainate receptor . since native ka receptors are heterogeneous , the properties of example 5 were also examined in recombinant glur6 receptors . these receptors exhibit saturable 3 h ! kainate binding and produce rapidly desensitizing currents in response to ka and glutamate characteristic of native ka receptors . the k d of 3 h ! kainate at glur6 has previously been reported between 12 . 9 and 95 nm , and the k d obtained in this study is consistent with the former values . differences in apparent affinity of 3 h ! kainate may be attributable to both the expression systems and assay methods employed . the potency of example 5 to inhibit 3 h ! kainate binding to glur6 was comparable to ka , and the increase in k d of 3 h ! kainate ( without a change in b max ) observed in the presence of example 5 is consistent with a competitive mode of action . based on the rank order of potencies of ka , domoate and ns - 102 , it has been concluded that glur6 most closely resembles the &# 34 ; low &# 34 ; affinity form of ka receptors . in view of the apparent heterogeneity of wild type ka receptors , the observation that the apparent affinity of example 5 was essentially equal to that of ka at glur6 but 2 - 3 fold lower at both the &# 34 ; high &# 34 ; and &# 34 ; low &# 34 ; affinity forms of native ka receptors in rat brain indicates example 5 may exhibit selectivity for some receptor subtypes . in combination , in vitro and in vivo assays are predictive of the activity of these compounds for treatment of patients . this is supported , for example , by u . s . pat . no . 5 , 061 , 721 to cordi et al . on the use of a combination of d - cycloserine and d - alanine to treat alzheimer &# 39 ; s disease , age - associated memory impairment , learning deficits , and psychotic disorders , as well as to improve memory or learning in healthy individuals , and u . s . pat . no . 5 , 086 , 072 to trullas et al . on 1 - aminocyclo - propane carboxylic acid ( acpc ), which modulates the nmda receptor . as is now being tested in clinical trials , acpc and its derivatives can be used to treat neuropharmacological disorders resulting from excessive activation of the nmda receptor , such as occurs in ischemia . nmda antagonists and partial agonists have clearly been shown to be useful in human clinical trials based on in vitro and in vivo assays , as described by hutchinson , et al ., j . med . chem . 32 , 2171 - 2178 ( 1989 ). hutchinson , et al ., ( 1989 ) reported that 4 -( phosphonomethyl )- 2 - piperidine carboxylic acid ( cgs - 19755 ), a competitive glutamate antagonist for the nmda receptor , is active in animal models of neurodegenerative diseases such as stroke and is currently undergoing human clinical evaluation for the treatment of strokes and head trauma . the following tests are used to demonstrate that binding activity correlates with physiological activity , both in vitro and in vivo . the results of these tests indicate that kainate antagonists and partial agonists will be effective clinically for treatment of a variety of disorders , including includes cognitive , learning , and memory deficits , chemical toxicity ( including substance tolerance and addiction ), excitotoxicity , neurodegenerative disorder ( such as huntington &# 39 ; s disease , parkinson &# 39 ; s disease , and alzheimer &# 39 ; s disease ), post - stroke sequelae , epilepsy , seizures , mood disorders ( such as bipolar disorder , dysthymia , and seasonal affective disorder ), depression , and pain . neurodegenerative disorders can result from dysfunction or malfunction of the receptor . tissue slice or whole cell electrophysiology as described by yamada ( neurophysiology , 1994 and references therein ) is used to measure agonist , partial agonist , or antagonist properties of drugs for glutamate receptors . this is a useful assay to demonstrate the in vivo activity of compounds such as those described herein , since it is predictive of efficacy , defined as the potency of the compound . this is distinct from the binding affinity . for example , whole cell electrophysiology shows that the compound of example 8 , ( 2s , 4r )- 4 - methyl glutamic acid , modulates the ka but not the ampa receptor . rat glur6 ka receptors were expressed in hek 293 cells in culture and evaluated by the patch clamp technique . ( 2s , 4r )- 4 - methyl glutamic acid at doses of 10 nm to 20 μm completely and reversibly blocked the current evoked by 300 mm ka . ( 2s , 4r )- 4 - methyl glutamic acid can be administered in combination with a ka block several times without damage to the cells . in contrast , when rat glur4 ( ampa ) receptors were expressed in hek 293 cells , concentrations of ( 2s , 4r )- 4 - methyl glutamic acid up to 200 μm had no effect on currents evoked by 300 μm ampa . the same type of experiment was repeated with rat dorsal root ganglia in culture which express a high level of glur5 ka receptors . 20 to 40 μm of ( 2s , 4r )- 4 - methyl glutamic acid completely and reversibly blocked 300 μm ka induced currents . when the ( 2s , 4r )- 4 - methyl glutamic acid was tested against the glur4 ampa receptor expressed in hek 293 cells , doses up to 200 μm did not inhibit 300 μm ampa currents , which demonstrate its selective modulation of ka versus ampa receptors . it is expected that the other compounds described herein will also selectively modulate the ka receptor . the following assays can also be used to evaluate the physiological activity and potency of the compounds described herein . this assay is used to determine the extent of protection afforded by a test compound on neural brain cells subjected to ischemic conditions as a model of neurodegeneration . male mongolian gerbils are injected with the test compound prior to carotid occlusion . flow is occluded for 4 to 5 min . and then opened and inspected to confirm reflow . following surgery , the gerbils are kept alive for 7 days . they are anesthetized with pentobarbital and perfused transcardially with saline with heparin followed by buffered formalin . the brain is removed , trimmed , and prepared for histological processing . sections are stained and damaged neurons in the ca1 region of the hippocampus are examined . the effects of the test compound are compared to untreated controls . based on the in vitro results described above , it is expected that cell loss will be significantly reduced in gerbils treated with the compounds described herein . this test is to determine the extent of protection by a test compound to neuropathic pain sensations . the model is described by bennett , neuro . report 5 , 1438 - 1440 ( 1994 ), and references cited therein . a rat is prepared by bilaterally exposing the sciatic nerves on both thighs . on one side , loosely fitting constrictive ligatures are tied around the nerve ; the other side is sham manipulated but ligated . with the rat standing on an elevated perforated floor , mechano - allodynia is measured by applying from beneath a graded series of yon frey hairs to the mid - plantar region of the effected paws . the hair that evokes at least one withdrawal response is designated the threshold level when compared to the sham treated nerve . this test is to determine the extent of antidepressant activity of a test compound . the model described by trullas , et al ., eur . j . pharm . 185 , 1 - 10 ( 1990 ), and the references cited therein . mice are placed individually in a cylinder filled with water at 22 °- 25 ° c . the duration of immobility is scored during the last four minutes of a six minute test . kainate administered locally or cocaine administered subcutaneous ( s . c .) induces an increase in dopamine release in nucleus accumbens and nucleus caudatus accompanied by stereotype behavior such as hyper - locomotion , rearing , sniffing , and grooming . these effects can be inhibited by ka receptor antagonists administered locally or systemically . based on these observations , it has been concluded that non - nmda receptors regulate the release of dopamine in the nucleus caudatus and that non - nmda receptors antagonists can alleviate the symptoms of psychosis . the compounds described herein should thereof eliminate or inhibit kainic acid or cocaine induced behavior . the compounds described herein can be administered parenterally , either subcutaneously , intramuscularly , or intravenously , or alternatively , administered orally in a dose range of between approximately 0 . 1 mg / kg body weight and 150 mg / kg body weight . the active ingredient can be administered parenterally , in sterile liquid dosage forms . in general , water , a suitable oil , saline , aqueous dextrose , and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions . solutions for parenteral administration preferably contain a water soluble form of the active ingredient , suitable stabilizing agents , and , if necessary , buffer substances . antioxidizing agents such as sodium bisulfite , sodium sulfite , or ascorbic acid , either alone or in combination , can be used as suitable stabilizing agents . also used are citric acid and its salts and sodium edta . in addition , parenteral solutions can contain preservatives , such as benzalkonium chloride , methyl - or propylparaben , and chlorobutanol . the active ingredient can be administered orally in solid dosage forms , such as capsules , tablets and powders , or in liquid dosage forms , such as elixirs , syrups , and suspensions . gelatin capsules contain the active ingredient and powdered carriers , such as lactose , starch , cellulose derivatives , magnesium stearate , or stearic acid . similar diluents can be used to make compressed tablets . both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours . compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere . other agents that can be used for delivery include liposomes , microparticles ( including microspheres and microcapsules ), and other release devices and forms that provide controlled , prolonged or pulsed , delivery or which enhance passage through the blood brain barrier , for example . bioerodible microspheres can be prepared using any of the methods developed for making microspheres for drug delivery , for example , as described by mathiowitz and langer , j . controlled release 5 , 13 - 22 ( 1987 ); mathiowitz , et al ., reactive polymers 6 , 275 - 283 ( 1987 ); and mathiowitz , et al ., j . appl . polymer sci . 35 , 755 - 774 ( 1988 ), the teachings of which are incorporated herein . the selection of the method depends on the polymer selection , the size , external morphology , and crystallinity that is desired , as described , for example , by mathiowitz , et al ., scanning microscopy 4 , 329 - 340 ( 1990 ); mathiowitz , et al ., j . appl . polymer sci . 45 , 125 - 134 ( 1992 ); and benita , et al ., j . pharm . sci . 73 , 1721 - 1724 ( 1984 ), the teachings of which are incorporated herein . methods routinely used by those skilled in the art include solvent evaporation , hot melt encapsulation , solvent removal , spray drying , phase separation and ionic crosslinking of gel - type polymers such as alginate or polyphosphazines or other dicarboxylic polymers to form hydrogels . other delivery systems including films , coatings , pellets , slabs , and devices can be fabricated using solvent or melt casting , and extrusion , as well as standard methods for making composites . the microparticles can be suspended in any appropriate pharmaceutical carrier , such as saline , for administration to a patient . in the most preferred embodiment , the microparticles will be stored in dry or lyophilized form until immediately before administration . they will then be suspended in sufficient solution for administration . the polymeric microparticles can be administered by injection , infusion , implantation , orally , or administration to a mucosal surface , for example , the nasal - pharyngeal region and / or lungs using an aerosol , or in a cream , ointment , spray , or other topical carrier , for example , to rectal or vaginal areas . the other devices are preferably administered by implantation in the area where release is desired . the materials can also be incorporated into an appropriate vehicle for transdermal delivery as well as stents . appropriate vehicles include ointments , lotions , patches , and other standard delivery means . modifications and variations of the present invention will be obvious to those skilled in the art from the foregoing detailed description . such modifications and variations are intended to come within the scope of the appended claims .