A series of α2/3-subtype selective GABAA receptor agonist imidazodiazepine(IBZ) PAMS were synthesized and investigated, Among them HZ-166 one of the initial lead compounds which has anxiolytic ,antinociceptive effect inagainst neuropathic and inflammatory pain and anticonvulsant effects. It shows also stability in human liver microsomes (HMLs) but it is not as stable in mouse liver microsomes due to its ester function which hydrolysis to carboxylic acid. To prevent this metabolism in mouse livers different types of bioisosteres have been synthesized, among them KRM-ii-81 shows promising result which is was shown by α2/3 GABAergic subtype selectivity in HEK cells, liver microsomal stability and anxiolytic activity. In addition, there was no sedation nor ataxia rotarod assay in mice (80mg/Kg) and Rats (300 mg/Kg). In comparison with HZ-I-66, KRM-II-81 was found to be a better anticonvulsant, anxiolytic and more active against neuropathic and inflammatory pain. KRM-II-81 had much greater BBB penetration, as indicated by the high concentration of compound found within brain samples two hours after oral administration, whereas HZ-I-66 was below the quantifiable limit (&lt; 12 nM). The results of these studies indicate that KRM-II-81 or its analogs have great potential to advance to clinical trials as non-sedating anxiolytic, anticonvulsant and antinociceptive agents, which do not develop tolerance to the anticonvulsant or antinociceptive effects.

Anxiolytic, antinociceptive and anticonvulsant effect of α2/3-subtype selective GABAA receptor agonist KRM-ii-81

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.