Pharmacology in translation: the preclinical and early clinical profile of the novel α2/3 functionally selective GABA_A receptor positive allosteric modulator PF-06372865.

ABSTRACT:

Background and purpose

Benzodiazepines, non-selective positive allosteric modulators (PAMs) of GABA_A receptors, have significant side effects that limit their clinical utility. As many of these side effects are mediated by the α1 subunit, there has been a concerted effort to develop α2/3 subtype-selective PAMs.

Experimental approach

In vitro screening assays were used to identify molecules with functional selectivity for receptors containing α2/3 subunits over those containing α1 subunits. In vivo receptor occupancy (RO) was conducted, prior to confirmation of in vivo α2/3 and α1 pharmacology through quantitative EEG (qEEG) beta frequency and zolpidem drug discrimination in rats respectively. PF-06372865 was then progressed to Phase 1 clinical trials.

Key resul

SUBMITTER: Nickolls SA 

PROVIDER: S-EPMC5786456 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature