Lawrence Leo Martin

Stereoselective R-(+) enantiomer of HA-966 displays anxiolytic effects in rodents

Anxiolytic agents disinhibit suppressed behaviors in rodents in preclinical models of anxiety such as the non-conditioned social interaction and elevated plus maze assays and the conditioned conflict Cook and Davidson procedure. The (+) and (-) enantiomers of (+/-)-3-amino-1-hydroxy-2-pyrrolidinone (HA-966) have been resolved and revealed that R-(+)-HA-966 significantly disinhibits both non-conditioned and conditioned suppressed behavior similar to the benzodiazepine diazepam, while the S-(-) enantiomer was devoid of anxiolytic activity and only produced behavioral sedation. Furthermore, R-(+)-HA-966 lacked side-effects in rodents commonly associated with the administration of benzodiazepines such as motor incoordination and ataxia, significant interactions with ethanol, and amnesia. These data suggest that R-(+)-HA-966, an antagonist at the strychnine-insensitive glycine/NMDA receptor site, was anxioselective and lacked some of the side-effects associated with benzodiazepine anxiolytics.

Synthesis and preliminary structure-activity relationships of 1-[(3-fluoro-4-pyridinyl)amino]-3-methyl-1H-indol-5-yl methyl carbamate (P10358), a novel acetylcholinesterase inhibitor

Abstract A series of carbamate analogs of besipirdine (HP 749) was synthesized as potential agents with enhanced cholinomimetic properties for the treatment of Alzheimers disease. Compound 5a (P10358, 1-[3-fluoro-4-pyridinyl)amino]-3-methyl-1H-indol-5-yl methyl carbamate) emerged as a potent, reversible acetylcholinesterase inhibitor that significantly enhanced performance on oral or parenteral administration in learning and memory paradigms.

4-aminopyridine derivatives: A family of novel modulators of voltage-dependent sodium channels

The interactions of a family of aminopyridine derivatives with Site II of the voltage‐dependent sodium channel were examined by measuring the ability of these compounds to inhibit [3H]batrachotoxin binding and veratridine‐induced increases in [Ca2+]i. Aminopyridines substituted with indole, carbazole, and pyrrole rings were evaluated. All compounds that had an aromatic ring linked to the amine group of 4‐aminopyridine showed positive results in both assays. For example, the most potent compound, besipirdine (N‐(n‐propyl)‐N‐(4‐pyridinyl)‐1H‐indol‐1‐amine), had IC50 values of 5 μM and 23.8 μM in the two assays, respectively. Small substitutions on either the aromatic ring or on 4‐aminopyridine did not substantially change their potencies. Indoles linked to the amino group of 2‐ and 3‐aminopyridine also showed positive results. These results indicate that aminopyridine derivatives substituted with an aromatic ring on the amino nitrogen are inhibitors of voltage‐dependent sodium channels. Drug Dev. Res. 44:8–13, 1998.

Toxicity of acids and bases after intraperitoneal injection.

Abstract Acetic acid, injected intraperitoneally, was lethal for mice housed in an incubator (37°C) and in the cold room (5°C), but not at room temperature (23°C). A dose of 4 meq/kg killed over 50% of the mice within 4 hr at the extremes of temperature, and none at 23°C. This difference in mortality was also obtained with other irritating acids and bases at the same dose, but not their salts. This effect was dose dependent with respect to the milliequivalency of injected agent. The cause of death is unknown. Poikilothermia was induced with the lethal agents at all 3 temperatures. Pretreatment of the mice with various pharmacologic agents did not prevent death. Autopsy of animals sacrificed just prior to death revealed necrosis of the mucosa and a peritoneal exudate in acid-treated animals; this pathology was judged identical at 23°C and 37°C with the same dose of acid. This pattern of mortality and poikilothermia resembles that obtained with endotoxin in mice, and may provide a simple, reproducible model for studying “endotoxic” death in mice, as well as its possible pharmacologic prevention.