The behavioral pharmacology of NMDA receptor antagonists.

There is considerable interest in the development of NMDA antagonists as potential therapeutic agents in the treatment of convulsant, neurodegenerative and anxiety disorders. Because the clinical use of phencyclidine (PCP) has been precluded by its psychotomimetic effects and abuse potential, there has been concern that other NMDA antagonists including those acting competitively might produce similar untoward effects. However, the studies in animals, reviewed here by Joyce Willetts, Robert Balster and David Leander, suggest that while there are certain similarities in the behavioral effects of PCP-like and competitive antagonists, there are also differences. These differences have implications for the development of NMDA antagonists with less likelihood for producing PCP-like side-effects.

Buprenorphine has potent kappa opioid receptor antagonist activity.

Buprenorphine was studied for its effects on urinary output to determine if it was an agonist, partial agonist, or antagonist at the kappa receptor. Buprenorphine was a potent antagonist of bremazocine-induced urination and had no kappa agonist activity. Thus, the high affinity that buprenorphine has for the kappa receptor results in potent kappa receptor antagonist activity in vivo.

Effects of ketazocine, ethylketazocine and phenazocine on schedule-controlled behavior: antagonism by naloxone.

Dose-effect curves were determined for phenazocine (0.64-2.5 mg/kg), ketazocine (1.25-80 mg/kg) and ethylketazocine (1.25-80 mg/kg) in pigeons responding under a multiple fixed-ratio 30-response, fixed-interval 5-min schedule of grain presentation. All three opioid agonists decreased responding with the larger doses. The effects of phenazocine were completely antagonized by small doses of naloxone (0.01-1 mg/kg), whereas the effects of ethylketazocine required larger doses of naloxone (1-10 mg/kg) to be completely antagonized. The behavioral effects of ketazocine were partially attenuated by naloxone, but were not antagonized completely even by a 10 mg/kg dose of naloxone. These data from the pigeon are consistent with previous interpretations that the effects of phenazocine are mediated by actions at a mu opioid receptor, whereas the effects of ketazocine and ethylketazocine are mediated by actions at a kappa opioid receptor.

Meperidine-induced hypothermia in the rat.

A dose of 40 mg/kg of meperidine (pethidine) caused a marked lowering of rectal temperature in restrained female rats at room temperature (22 degrees C). This decrease was not antagonized by injection of 1 mg/kg of naloxone, whereas hypothermia of equal magnitude induced by 20 mg/kg of morphine was reversed by 1 mg/kg of naloxone. Pretreatment with the serotonin reuptake blocker, fluoxetine (10 mg/kg), or a non-hypothermic dose of meperidine (20 mg/kg) significantly potentiated the hypothermia induced by 100 mg/kg of l-5-hydroxytryptophan. The hypothermic effect of 40 mg/kg of meperidine was significantly greater than that of 10 mg/kg of fluoxetine. Finally, 40 mg/kg of meperidine produced a significantly greater hypothermic effect in restrained rats than in unrestrained rats. The results indicate that the hypothermic effect of meperidine is not a result of an opioid action, and that although it may be mediated through serotonergic systems, inhibition of serotonin reuptake is probably not the primary mechanism.

Anticonvulsant effects of a novel aminobenzamide (LY201116) in mice.

The drug 4-amino-N-(2,6-dimethylphenyl)benzamide(LY201116) is a potent and selective anticonvulsant in the maximal electric shock test in mice. The ED50 values after oral and intravenous administration were 1.7 mg/kg and 0.51 mg/kg, respectively. For comparison, the oral and intravenous ED50 values for the anticonvulsant phenytoin which is selective for the maximal electric shock test were 9.1 and 8.5 mg/kg, respectively. After oral administration, LY201116 had a protective index (ED50 to produce neurological impairment, divided by ED50 on the maximal electric shock) of 13.5. After 4 days of administration, there was no evidence of the development of tolerance to the anticonvulsant effects of LY201116. The hexobarbital-induced sleeping time was not significantly affected by either acute or chronic administration of LY201116 for 4 days. In combination studies with the anticonvulsants phenytoin and carbamazepine which are selective for the maximal electric shock test, LY201116 produced dose-additive effects which suggest that it produces its anticonvulsant action through the same mechanism of action as these prototype anticonvulsants.

In vitro and in vivo antagonism of AMPA receptor activation by (3S, 4aR, 6R, 8aR)-6-[2-(1(2)H-tetrazole-5-yl) ethyl] decahydroisoquinoline-3-carboxylic acid.

The in vitro and in vivo pharmacology of a structurally novel competitive antagonist for the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) subtype of excitatory amino acid receptors is described. LY215490, (+/-)(6-(2-(1-H-tetrazol-5-yl)ethyl) decahydroisoquinoline-3-carboxylic acid), was shown to displace selectively 3H-AMPA and 3H-6-cyano-7-nitro- quinoxaline-2,3-dione (3H-CNQX) binding to rat brain membranes. LY215490 potently antagonized quisqualate-and AMPA-induced depolarizations of rat cortical slices in a competitive manner, while requiring higher concentrations to antagonize the effects of N-methyl-D-aspartate (NMDA) and kainate. In slices of rat hippocampus, LY215490 also selectively antagonized AMPA-evoked release of 3H-norepinephrine. These AMPA receptor activities were due to the (-) isomer of the compound. (3S,4aR,6R, 8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl] decahydroisoquinoline-3-carboxylic acid (LY293558). LY215490 was centrally active following parenteral administration in mice as demonstrated by protection versus maximal electroshock seizures and decreases in spontaneous motor activity. LY215490 (its active isomer being LY293558) represents a novel pharmacological agent for in vitro and in vivo studies of AMPA receptor function in the CNS.

Imidazole anticonvulsants: structure-activity relationships of [(biphenylyloxy)alkyl]imidazoles.

The [(biphenylyloxy)alkyl]imidazoles were found to be potent anticonvulsants. The most potent compound of the series, 1-[2- ([1,1'-biphenyl]-2-yloxy)ethyl]-1H-imidazole (4), had an ED50 of 15.5 mg/kg against maximal-electroshock-induced seizures in mice after oral administration; the horizontal screen ED50 was 320 mg/kg, revealing that the compound has a protective index of 21. Homologues bearing three- and four-carbon tethers between the imidazole and biphenylyloxy moieties were also active, but their potency was attenuated relative to 4. Congeners with the imidazolylalkoxy moiety at the meta or para positions of biphenyl were also less active. All these compounds were potent potentiators of hexobarbital-induced sleeping time in mice, presumably via the well-known imidazole-mediated inhibition of cytochrome P-450. The structural features governing the anticonvulsant and sleeping-time activities appear to be distinct, but a complete dissociation of these two effects has not been achieved. Thus, the potential of these compounds as clinically useful antiepileptic drugs would appear to be limited.

Absolute configurations and pharmacological activities of the optical isomers of fluoxetine, a selective serotonin-uptake inhibitor.

Fluoxetine is a potent and selective inhibitor of the neuronal serotonin-uptake carrier and is a clinically effective antidepressant. Although fluoxetine is used therapeutically as the racemate, there appears to be a small but demonstrable stereospecificity associated with its interactions with the serotonin-uptake carrier. The goals of this study were to determine the absolute configurations of the enantiomers of fluoxetine and to examine whether the actions of fluoxetine in behavioral tests were enantiospecific. (S)-Fluoxetine was synthesized from (S)-(-)-3-chloro-1-phenylpropanol by sequential reaction with sodium iodide, methylamine, sodium hydride, and 4-fluorobenzotrifluoride. (S)-Fluoxetine is dextrorotatory (+1.60) in methanol, but is levorotatory (-10.85) in water. Fluoxetine enantiomers were derivatized with (R)-1-(1-naphthyl)ethyl isocyanate, and the resulting ureas were assayed by 1H NMR or HPLC to determine optical purities of the fluoxetine samples. Both enantiomers antagonized writhing in mice; following sc administration of (R)- and (S)-fluoxetine, ED50 values were 15.3 and 25.7 mg/kg, respectively. Moreover, both enantiomers potentiated a subthreshold analgesic dose (0.25 mg/kg) of morphine, and ED50 values were 3.6 and 5.7 mg/kg, respectively. Following ip administration to mice, the two stereoisomers antagonized p-chloroamphetamine-induced depletion of whole brain serotonin concentrations. ED50 values for (S)- and (R)-fluoxetine were 1.2 and 2.1 mg/kg, respectively. The two enantiomers decreased palatability-induced ingestion following ip administration to rats; (R)- and (S)-fluoxetine reduced saccharin-induced drinking with ED50 values of 6.1 and 4.9 mg/kg, respectively. Thus, in all biochemical and pharmacological studies to date, the eudismic ratio for the fluoxetine enantiomers is near unity.

Preparation and anticonvulsant activity of a series of functionalized alpha-heteroatom-substituted amino acids.

Potent anticonvulsant activity has been reported for (R,S)-2-acetamido-N-benzyl-2-methylacetamide (2a). Select alpha-heteroatom substituted derivatives of 2a have been prepared (26 examples) in which the alpha-methyl group has been replaced by nitrogen (3a-q), oxygen (3r-u), and sulfur (3v-z) containing moieties. The functionalized amino acid derivatives were evaluated in the maximal electroshock seizure (MES) and horizontal screen (tox) tests in mice. The most active compounds were (R,S)-2-acetamido-N-benzyl-2-(methoxyamino)acetamide (31), and (R,S)-2-acetamido-N-benzyl-2-(methoxymethylamino)acetamide (3n). After ip administration, the MES ED50 values for 31 (6.2 mg/kg) and 3n (6.7 mg/kg) compared favorably with phenytoin (9.50 mg/kg).

Preparation and anticonvulsant activity of a series of functionalized alpha-aromatic and alpha-heteroaromatic amino acids.

We recently reported the potent anticonvulsant activity of (R,S)-alpha-acetamido-N-benzyl-alpha-phenylacetamide (2b). Selectively substituted derivatives of this compound have now been prepared (23 examples) and evaluated in the maximal electroshock seizure (MES) and horizontal screen (tox) tests in mice. In several key cases, replacement of the alpha-phenyl substituent in 2b by a relatively small, electron-rich, heteroaromatic moiety led to a substantial improvement in the anticonvulsant potency of the drug candidate. The most active compounds were (R,S)-alpha-acetamido-N-benzyl-2-furanacetamide (2g) and (R,S)-alpha-acetamido-N-benzyl-2-pyrroleacetamide (2i). After ip administration, the MES ED50 values for 2g (10.3 mg/kg) and 2i (16.1 mg/kg) compared well with phenytoin (9.50 mg/kg). Evaluation of the two individual enantiomers of 2g demonstrated that the anticonvulsant activity resided in the R stereoisomer. The low ED50 value (3.3 mg/kg) for (R)-2g contributed to the large protective index (TD50/ED50) observed for this drug candidate, which approached that of phenytoin.

Synthesis and anticonvulsant activities of alpha-heterocyclic alpha-acetamido-N-benzylacetamide derivatives.

Earlier studies showed that (R,S)-alpha-acetamido-N-benzylacetamides (2) containing a five- and six-membered aromatic or heteroaromatic group appended at the C(alpha) site displayed outstanding activity in the maximal electroshock-induced seizure (MES) test in mice. An expanded set of C(alpha)-heteroaromatic analogues of 2 have been prepared and evaluated. The observed findings extended the structure-activity relationships previously discerned for this novel class of anticonvulsants and have validated previous trends. The alpha-furan-2-yl (4), alpha-oxazol-2-yl (18), and alpha-thiazol-2-yl (19) alpha-acetamido-N-benzylacetamides afforded excellent protection against MES-induced seizures in mice. The ED50 and PI values for these adducts rivaled those reported for phenytoin. The outstanding properties provided by 4 led to an in-depth examination of the effect of structural modification at key sites within this compound on biological activity. The pharmacological data in this series indicated that stringent steric and electronic requirements existed for maximal activity and revealed the outstanding activity of (R)-(-)-alpha-acetamido-N-(4-fluorobenzyl)-alpha-(furan-2-yl)aceta mide [(R)-30].

Synthesis and analgesic properties of N-substituted trans-4a-aryldecahydroisoquinolines.

A representative series of N-substituted derivatives of the morphine-based trans-4a-aryldecahydroisoquinoline were synthesized and evaluated for opioid analgesic activities. Compounds with potent analgesic activity and high affinities for the mu and kappa opioid receptors were discovered. The effect of varying the N-substituent in the trans-4a-aryldecahydroisoquinoline paralleled, to a certain extent, previous findings with other morphine part structures. Replacement of the N-methyl with a phenethyl group significantly increased analgesic potency. The N-cyclopropylmethyl analogue was found in rodents to have mixed agonist-antagonist properties; however, its antagonist activity was far weaker than those reported for the N-(cyclopropylmethyl)morphinan and -benzomorphan derivatives. Resolution of the stereoisomers and determination of their absolute configuration by X-ray crystallography showed that the opioid receptor effects were predominantly found with the 4aR,8aR isomer, the same relative absolute configuration of morphine. Unexpectedly, the 4aR,8aR N-cyclopropylmethyl analogue (compound 30), which in rodents had mixed agonist-antagonist properties similar to those of pentazocine, was found in rhesus monkeys to behave as a full morphine-like agonist.

Discovery and anticonvulsant activity of the potent metabolic inhibitor 4-amino-N-(2,6-dimethylphenyl)-3,5-dimethylbenzamide.

Compound 2 [4-amino-N-(2,6-dimethylphenyl)benzamide] is an effective anticonvulsant in several animal models. For example, following oral administration to mice, it antagonized maximal electroshock (MES) induced seizures with an ED50 of 1.7 mg/kg. During drug disposition studies with 2, we found that it was rapidly metabolized by N-acetylation. Thirty minutes after oral administration of 1.7 mg/kg of 2 to mice, plasma concentrations of parent drug and the N-acetyl metabolite 5 were 1.09 and 0.41 microgram/mL, respectively. Six hours postadministration the concentrations were 0.23 and 0.22 microgram/mL, respectively. In order to sterically preclude or diminish the rate of metabolic N-acetylation, we synthesized analogues of 2 possessing either one (3) or two (4) methyl groups ortho to the 4-amino substituent. Both compounds antagonized MES-induced seizures after administration to mice; oral ED50 values for 3 and 4 were 3.5 and 5.6 mg/kg, respectively. Compound 3 was rapidly metabolized by N-acetylation. However, 4 provided exceptionally high and long-lived plasma concentrations of parent drug; no N-acetyl metabolite could be detected. While 2 and 3 had no pharmacologically relevant effects on hexobarbital-induced sleeping time in mice, 4 was a potent, dose-dependent potentiator of sleeping time. Oral administration of 375 micrograms/kg led to a 61% increase in sleeping time relative to control values. Thus, 4 represents one of the most potent potentiators of hexobarbital-induced sleeping time described to date.

4-(Tetrazolylalkyl)piperidine-2-carboxylic acids. Potent and selective N-methyl-D-aspartic acid receptor antagonists with a short duration of action.

We have prepared a series of cis-4-(tetrazolylakyl)piperidine-2-carboxylic acids as potent and selective N-methyl-D-aspartic acid (NMDA) receptor antagonists. NMDA antagonists may prove to be useful therapeutic agents, for instance, as anticonvulsants, in the treatment of neurodegenerative disorders such as Alzheimer's disease and in the prevention of neuronal damage that occurs during cerebral ischemia. The compounds prepared were evaluated in vitro in both receptor binding assays [( 3H]CGS-19755, [3H]AMPA, and [3H]kainic acid) and in a cortical-wedge preparation (versus NMDA, quisqualic acid, and kainic acid) to determine affinity, potency, and selectivity. The new amino acids were also evaluated in vivo for their ability to block NMDA-induced convulsions in neonatal rats and NMDA-induced lethality in mice. The most potent compound of this series, 15 (LY233053), selectively displaced [3H]CGS-19755 binding with an IC50 of 107 +/- 7 nM and selectively antagonized responses due to NMDA in a cortical-wedge preparation with an IC50 of 4.2 +/- 0.4 microM. Compound 15 blocked both NMDA-induced convulsions in neonatal rats (minimum effective dose (MED) = 20 mg/kg ip) and NMDA-induced lethality in mice (MED = 5 mg/kg ip). This is the first example of an NMDA receptor antagonist that incorporates a tetrazole moiety as an omega-acid bioisostere. These amino acid antagonists are also unique from their phosphonic acid counterparts in that they have a shorter duration of action in vivo. For the treatment of acute disorders such as stroke, where an NMDA antagonist would be administered parenterally, the shorter duration of action may be beneficial, e.g., allowing for better dosage control. The combination of potent NMDA receptor antagonism and a short duration of action may make these compounds useful therapeutic agents in the treatment of a variety of neurological disorders.

Synthesis and pharmacological evaluation of a major metabolite of ameltolide, a potent anticonvulsant.

The 4-aminobenzamides have provided several anticonvulsants that have been extensively investigated. Ameltolide, 4-amino-N-(2,6-dimethylphenyl)benzamide (compound 2,LY201116), is the most potent analogue studied to date. This drug is inactivated in vivo by metabolic N-acetylation and addition of a hydroxy moiety to one of the methyl substituents, resulting in compound 7,N-[4-[[[2-(hydroxymethyl)-6- methylphenyl] amino] carbonyl] phenyl] acetamide. This metabolite was prepared in five steps from a readily available starting material. Compound 7 and its nonacetylated analogue 6 were compared to ameltolide as anticonvulsants. After oral administration to mice, the MES ED50 values of ameltolide, 6, and 7 were 1.4, 10.9, and greater than 100 mg/kg, respectively, demonstrating that hydroxylation and acetylation dramatically decrease the anticonvulsant potency of ameltolide. This rank order of MES anticonvulsant potency was also seen after iv administration to mice, suggesting that these data reflect intrinsic pharmacological activities. After oral administration of 2.0 mg/kg of ameltolide to mice, parent drug, N-acetyl metabolite 3, and the hydroxy metabolite 7 were detected in plasma; the Cmax values were 572, 387, and 73 ng/mL, respectively. Compound 7 was the primary metabolite excreted in urine. These data indicate that 7 is a major metabolite of ameltolide, but does not contribute significantly to the pharmacological effects seen after administration of ameltolide to mice.

NMDA antagonist activity of (+/-)-(2SR,4RS)-4-(1H-tetrazol-5-ylmethyl)piperidine-2-carboxylic acid resides with the (-)-2R,4S-isomer.

The tetrazole-substituted amino acid (+/-)-(2SR,4RS)-4-(1H-tetrazol-5-ylmethyl)pip eri dine-2-carboxylic acid (LY233053, (+/-)-1) was resolved into its constituent enantiomers by treatment of a key intermediate in the synthesis of the racemic amino acid, ethyl (+/-)-cis-4-(cyanomethyl)-N-allylpiperidine-2-carboxylate, with either 2S,3S- or 2R,3R-di-p-toluoyltartaric acid. These resolved amines were then converted as for the racemate to the amino acids (-)-1 and (+)-1. The activity of this potent and selective NMDA antagonist was found to reside with the (-)-isomer of 1 (LY235723). X-ray crystallographic analysis of the 2S,3S-di-p-toluoyltartaric acid salt of ethyl cis-4-(cyanomethyl)-N-allylpiperidine-2-carboxylate showed that the resolved amine, and thus (-)-1, possessed the 2R,4S absolute stereochemistry. Affinity for the NMDA receptor was determined using the specific radioligand [3H]-(2SR,4RS)-4-(phosphonomethyl)piperidine-2-carboxylic acid ([3H]CGS 19755; IC50 = 67 +/- 6 nM), and selective NMDA antagonist activity was determined using a cortical slice preparation (IC50 versus 40 microM NMDA = 1.9 +/- 0.24 microM). This compound also demonstrated potent NMDA antagonist activity in vivo following systemic administration through its ability to block NMDA-induced convulsions in neonatal rats, NMDA-induced lethality in mice, and NMDA-induced striatal neuronal degeneration in rats.

Structure-activity relationships of (arylalkyl)imidazole anticonvulsants: comparison of the (fluorenylalkyl)imidazoles with nafimidone and denzimol.

A recently discovered and structurally distinct class of antiepileptic drugs is the (arylalkyl)imidazoles. Two independently discovered representatives of this class, denzimol (alpha-[4-(2-phenylethyl)phenyl]-1H-imidazole-1-ethanol) and nafimidone (2-(1H-imidazol-1-yl)-1-(2-naphthalenyl)ethanone), are undergoing clinical evaluation. Our structure-activity relationship (SAR) studies revealed that in addition to the naphthalenyl and phenethylphenyl aryl moieties of nafimidone and denzimol, respectively, fluorenyl, benzo[b]thienyl, and benzofuranyl aryl groups provided several highly active (arylalkyl)imidazole anticonvulsants. These structurally diverse aryl moieties, and comparable anticonvulsant activities, lend credence to the hypothesis that the pharmacophore of this class of anticonvulsants is the alkylimidazole portion of the molecule, with the lipophilic aryl portion enabling penetration of the blood-brain barrier. We focused our SAR studies on the (fluorenylalkyl)imidazole series. A representative compound from this series is 1-(9H-fluoren-2-yl)-2-(1H-imidazol-1-yl)ethanone. This agent was twice as potent as nafimidone in inhibiting maximal electroshock seizures in mice (po ED50's = 25 and 56 mg/kg, respectively) and considerably less toxic in the rat (po LD50's = 4550 and 504 mg/kg, respectively). The tertiary alcohol alpha-(9H-fluoren-2-yl)-alpha-methyl-1H-imidazole-1-ethanol was as potent as denzimol in mice (po ED50's = 10 and 12 mg/kg, respectively). This series of imidazole anticonvulsants was highly selective; while many compounds displayed potent antielectroshock activity, little or not activity was observed against pentylenetetrazole-induced clonic seizures or in the horizontal screen test for ataxia. All active compounds that we tested in this series, as well as denzimol and nafimidone, potentiated hexobarbital-induced sleeping time in mice, probably by imidazole-mediated inhibition of cytochrome P-450. The SAR's for the anticonvulsant activity and the sleeping time potentiation were similar. The propensity of these (arylalkyl)imidazole anticonvulsants to interact strongly with cytochrome P-450 and thereby impair the metabolism of other antiepileptic drugs may severely limit their clinical utility as anticonvulsants.

Discovery of a potent, peripherally selective trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonist for the treatment of gastrointestinal motility disorders.

Structure-activity relationship studies were pursued within N-substituted-trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines in an effort to discover a peripherally selective opioid antagonist with high activity following systemic administration. Altering the size and the polarity of the N-substituent led to the discovery of 3 (LY246736). Compound 3 has high affinity for opioid receptors (Ki = 0.77, 40, and 4.4 nM for mu, kappa, and delta receptors, respectively). It is a potent mu receptor antagonist following parenteral and oral administration and distributes selectively (> 200-fold selectivity) to peripheral receptors. Thus, 3 has properties suitable for the clinical investigation of mu opioid receptor involvement in GI motility disorders.

Structure-activity studies of 6-(tetrazolylalkyl)-substituted decahydroisoquinoline-3-carboxylic acid AMPA receptor antagonists. 1. Effects of stereochemistry, chain length, and chain substitution.

A series of 6-substituted decahydroisoquinoline-3-carboxylic acids were prepared as excitatory amino acid (EAA) receptor antagonists. These compounds are antagonists at the N-methyl-D-aspartate (NMDA) and 2-amino-3-(5-methyl-3-hydroxyisoxazol-4-yl) propanoic acid (AMPA) subclasses of ligand gated ion channel (ionotropic) EAA receptors. (3S,4aR, 6R,8aR)-6-(2-(1H-tetrazol-5-yl)ethyl)- 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (9) is a potent, selective and systemically active AMPA antagonist. Other analogs from this series, including (3S,4aR,6S,8aR)-6-((1H-tetrazol-5-yl)methyl)- 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (32) and (3S,4aR,6S,8aR)-6- (phosphonomethyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-ca rboxylic acid (61) are potent, selective, and systemically active NMDA antagonists. This and the subsequent publication look at the AMPA antagonist aspects of this SAR. Herein we report the effects of varying stereochemistry around the hydroisoquinoline ring; of tetrahydro-versus decahydroisoquinoline; of having the carboxylic acid at C-1 versus C-3; of varying the length of the carbon chain connecting a tetrazole to the bicyclic nucleus; and of holding the connecting chain constant at two atoms, the effect of heteroatom substitution in the position adjacent to the bicyclic nucleus and substitution with methyl or phenyl on the chain. Compounds were evaluated on rat cortical tissue for their ability to inhibit the binding of radioligands selective for AMPA ([3H]AMPA), NMDA ([3H]CGS 19755), and kainic acid ([3H]-kainic acid) receptors and for their ability to inhibit depolarizations induced by AMPA (40 microM), NMDA (40 microM), and kainic acid (10 microM). Our findings revealed that the optimal stereochemical array was the same for both NMDA (32 and 61) and AMPA (9) antagonists identified in this series and that the tetrahydroisoquinoline (25) and the C-1 carboxy (30) analogs of 9 are inactive. With a tetrazole in the distal acid position, an ethylene spacer (9) is optimal; substitution with oxygen or nitrogen on the chain in the position adjacent to the bicyclic nucleus significantly reduced activity, while substitution with a methyl or phenyl group on the chain was well tolerated.

Structure-activity studies of 6-substituted decahydroisoquinoline-3-carboxylic acid AMPA receptor antagonists. 2. Effects of distal acid bioisosteric substitution, absolute stereochemical preferences, and in vivo activity.

We have explored the excitatory amino acid antagonist activity in a series of decahydroiso-quinoline-3-carboxyic acids, and within this series found the potent and selective AMPA antagonist (3SR,4aRS,6RS,8aRS)-6-(2-(1H-tetrazol-5-yl )ethyl) decahydroisoquinoline-3-carboxylic acid (1). In this and the preceding paper, we looked at the structure-activity relationships for AMPA antagonist activity in this series of compounds. We have already shown that 1 had the optimal stereochemical array and that AMPA antagonist activity was maximized for a two-carbon spacer separating a tetrazole from the bicyclic nucleus. In this paper, we explored the effects of varying the distal acid and the absolute stereochemical preferences of many of these analogs. We looked at a variety of different acid bioisosteres, including 5-membered hetereocyclic acids such as tetrazole, 1,2,4-triazole, and 3-isoxazolone; carboxylic,phosphonic, and sulfonic acid; and acyl sulfonamides. Compounds were evaluated in rat cortical tissue for their ability to inhibit the binding of radioligands selective for AMPA ([3H]AMPA), NMDA ([3H]CGS 19755), and kainic acid ([3H]kainic acid) receptors and for their ability to inhibit depolarizations induced by AMPA (40 microM), NMDA (40 microM), and kainic acid (10 microM). A number of compounds from this and the preceding paper were also evaluated in mice for their ability to block maximal electroshock-induced convulsions and ATPA-induced rigidity in mice.