Benzylidene-substituted imidazo-thiazole-thiazine and -thiazepine derivatives: A new class of ligands for the benzodiazepine binding site of GABA(A) receptors

Abstract

A series of 15 benzylidene-substituted imidazo[2,1-b]thiazole, -thiazine, and -thiazepine derivatives was synthesized and investigated in radioligand binding studies at the benzodiazepine binding site of GABA(A) receptors in rat brain cortical membranes. New compounds could be identified which exhibit affinity for the benzodiazepine binding site in low micromolar concentrations. Analysis of the structure-activity relationships reveals that thiazepine (7-ring) and thiazine (6-ring) derivatives are more potent than analogous thiazole (5-ring) derivatives. Receptor affinity is strongly dependent on the substitution pattern of the benzylidene residue. The most potent compounds of the present series were Z-2-(2-chlorobenzylidene)-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazin-3( 2H)-one (5c) and its 3-chlorobenzylidene-substituted isomer 5b with K(i) values of 5.7 μM and 12 μM, respectively. Based on the determination of the GABA shift, 5b and 5c could be characterized as partial agonists.