Barry Dubinsky

Potential anxiolytic agents. 2. Improvement of oral efficacy for the pyrido[1,2-a]benzimidazole (PBI) class of GABA-A receptor modulators

Abstract We have further explored the structure-activity relationships of pyrido[1,2- a ]benzimidazole (PBI) derivatives (viz. prototype 1 ), a novel series of central GABA-A receptor modulators, with the intent of enhancing oral efficacy. A study involving the introduction of acidic or basic groups led to the identification of RWJ-38293 ( 3a ) as a potential anxiolytic agent.

Potential anxiolytic agents. 3. Novel A-ring modified pyrido[1,2-a]benzimidazoles

A variety of pyrido[1,2-a]benzimidazoles (PBIs) modified on the A-ring were prepared and evaluated for affinity to the benzodiazepine binding site on the GABA-A receptor and in animal models predictive of anxiolytic activity in humans. A-ring benzo-fused derivative 7 exhibited potent activity, as did the 6- and 7-pyrido compounds 3 and 4.

Potential Anxiolytic Agents. Part 4: Novel Orally-Active N5-Substituted Pyrido[1,2-a]benzimidazoles with High GABA-A Receptor Affinity

A series of pyrido[1,2-a]benzimidazoles (PBIs) with substitution on the N(5)-nitrogen has been synthesized and found to possess high affinity for the benzodiazepine (BZD) site on the GABA-A receptor. The compounds evaluated include those bearing a heteroalkyl group and heterocyclic rings. The most promising of these compounds is ethoxymethyl analogue 24, which has an IC(50) of 0.1 nM for the BZD site on the GABA-A receptor and has been advanced to human clinical trials.

Correlation of analgesia with levels of tilidine and a biologically active metabolite in rat plasma and brain

Abstract The analgesic ED 50 of tilidine administered orally to rats was 15.4 mg/kg at 15 min and 17.2 mg/kg at 30 min. The drug was metabolized quickly and extensively, and it and its principal metabolite readily crossed the blood-brain barrier. Analgesia after the oral administration of tilidine fumarate to rats was correlated with levels of this metabolite in plasma and brain, and with the tilidine levels in plasma. It appears probable that the conversion of tilidine into its metabolite. which has analgesic properties, is closely related to the analgesic state.

New directions in anxiolytic drug research

Agents to treat anxiety have gained in acceptance and importance in the fast pace of life in the second half of this century. The discovery and refinement of the benzodiazepines represented a quantum leap in therapy from early compounds which were essentially sedatives. With the advent of molecular biology, an understanding of the basic mechanism by which the benzodiazepines exert their effects was revealed through the discovery and isolation of the GABAA receptor and its benzodiazepine binding site. This, in turn, has enabled benzodiazepines to be classified into a broad spectrum of pharmacological types ranging from agonist to inverse agonist, thus allowing fine tuning with respect to side-effects. Consequently, newer, more promising agents have emerged which bind at the GABAA BZD site and have reduced side-effects. An example of this is RWJ-51204 (92), a member of a novel structural type which is superior to several marketed benzodiazepines in animals in terms of efficacy and side-effects. The cost-conscious environment of managed health care presents continuing challenges to the discovery and development of safe, highly efficacious, and cost-effective anxiolytic agents.