Imidazo[1,2-a]pyrimidines as Functionally Selective and Orally Bioavailable GABA_Aα2/α3 Binding Site Agonists for the Treatment of Anxiety Disorders

Abstract

A series of high-affinity GABA(A) agonists with good oral bioavailability in rat and dog and functional selectivity for the GABA(A)alpha2 and -alpha3 subtypes is reported. The 7-trifluoromethylimidazopyrimidine 14g and the 7-propan-2-olimidazopyrimidine 14k are anxiolytic in both conditioned and unconditioned animal models of anxiety with minimal sedation observed at full BZ binding site occupancy.

METABOLISM AND DISPOSITION OF A POTENT AND SELECTIVE GABA-Aα2/3 RECEPTOR AGONIST IN HEALTHY MALE VOLUNTEERS

“…1) is being developed as an anxiolytic for use in the treatment of GAD. The compound behaves as a potent GABA A receptor agonist with functional selectivity toward ␣ 2 and ␣ 3 receptor subtypes Carling et al, 2006;Goodacre et al, 2006b;Jennings et al, 2006;Russell et al, 2006). In animal models, it is an efficacious anxiolytic that lacks the side effects experienced with more nonselective GABA A receptor agonists.…”

Synthesis of 3-Arylimidazo[1,2-a]pyridines by a Catalyst-Free Cascade Process

“…1 Supporting Information for this article is available online at http://www.thieme-connect.com/ejournals/toc/synthesis…”

Structural basis for ligand recognition at the benzodiazepine binding site of GABAA α3 receptor, and pharmacophore-based virtual screening approach

“…The most promising model thus obtained could be used as 3D queries to search for new structural leads across publicly available multi conformational databases. To ensure structural diversity among the data set, 13 non-congeneric molecules known to exhibit functional selectivity were chosen as structural templates from literatures [15,[21][22][23][24][25][26][27][28][29].…”

“…The GABA A receptor, along with nicotinic acetylcholine receptor (nAChR), glycine receptor (GlyR) and 5-hydroxytryptamine (5-HT3) receptor, belongs to Cysloop super family of ligand-gated ion channels (LGIC) [2]. Of all these ion channels GABA A receptor has received the greatest attention in terms of research because of its importance as a biological target for clinically important drugs like barbiturates, neurosteroids, loreclezole, anesthetics, ethanol, and benzodiazepines (BDZs) [3,4]. The GABA A receptor is a membrane bound hetero pentameric complex arranged pseudo symmetrically around a central Cl À selective ion channel [5].…”