GABA _A Receptor Modulators

Abstract

Allosteric modulators are molecules that act at sites different from orthosteric sites and influence the effects of orthosteric ligands on the target protein. For the family of GABA A receptors, allosteric modulation is a key concept exploited by widely used pharmaceuticals, for example tranquilisers of the benzodiazepine type or sedative anaesthetics such as etomidate. Recent developments reflect efforts to identify the binding sites involved in such allosteric modulation and the selective targeting of individual receptor subtypes. The precise number and structures of native GABA A receptor subtypes are still not known. A widely used useful distinction refers to synaptic and extrasynaptic pools of receptors, and some progress has been made in targeting these pools separately. A recent surge identified endogenous modulators, among them endocannabinoids and dopamine. As knowledge about modulators as well as their binding sites increases, development of more selective agents will be facilitated. Key Concepts Clinically used drugs targeting GABA A receptors are mostly allosteric modulators – benzodiazepines and sedative narcotics are prominent examples. Allosteric modulators change agonist function in various ways by interactions with allosteric modulatory sites. Diverse effects have been categorised; acronyms such as PAM type I and similar are used – but the terminology is not standardised. Functional selectivity has been introduced as a term to differentiate selective action from selective binding. For many chemotypes the exact binding sites on GABA A receptors are not yet known; structural knowledge is still needed. While receptors consisting of alpha, beta and gamma subunits are very well characterised, much less is known about receptors that contain only alpha and beta subunits and receptors that contain delta, pi, theta, epsilon or rho subunits.