Synthesis and benzodiazepine receptor binding of some imidazo- and pyrimido[2,1-b]benzothiazoles

Article abstract of DOI:10.1016/0223-5234(96)89553-5

A series of substituted imidazo[2,1-b]benzothiazoles 2a-u was synthesized and the compounds evaluated for their affinity at the central benzodiazepine receptors. Substitution at the 7-position generally resulted in a decreased ligand affinity whereas a significant increase was observed for 5-substituted compounds. The intrinsic efficacy of selected high-affinity ligands 2j,k,q, as well as some previously reported pyrimido[2,1-b]benzothiazoles 1, was measured in vitro through the determination of the GABA ratio and [³⁵S]TBPS displacement. Consistent with a partial inverse agonist profile, the benzothiazole derivatives 2j,k,q increased [³⁵S]TBPS binding. For compounds 1c and 1d, a discrepancy between GABA ratio and [³⁵S]TBPS binding data was observed. Only the latter assay was in full agreement with the pharmacological data, which indicated an inverse agonist and a partial agonist profile for 2k,q and 1c,d respectively. The affinity and intrinsic activity data of compounds 1c,d and 2j,k,q are discussed in the light of the recently proposed pharmacophore model by Skolnick/Cook; in particular, the agonistic activity of 1c,d is interpreted on the basis of a possible interaction of substitutents in position 6 with the receptors lipophilic area L3 of Skolnick/Cook, whereas the observed inverse agonist profile of 2j,k,q is explained taking into account their structural analogy with the well known proconvulsant β-CCE.