SYNTHESIS AND BENZODIAZEPINE RECEPTOR-BINDING OF SOME IMIDAZO[2,1-B]BENZOTHIAZOLES AND PYRIMIDO[2,1-B]BENZOTHIAZOLES

A series of substituted imidazo[2,1-b]benzothiazoles 2a-u was synthesi zed and the compounds evaluated for their affinity at the central benz odiazepine receptors. Substitution at the 7-position generally resulte d in a decreased ligand affinity whereas a significant increase was ob served for 5-substituted compounds. The intrinsic efficacy of selected high-affinity ligands 2j,k,q, as well as some previously reported pyr imido[2,1-b]benzothiazoles 1, was measured in vitro through the determ ination of the GABA ratio and [S-35]TBPS displacement. Consistent with a partial inverse agonist profile, the benzothiazole derivatives 2j,k ,q increased [S-35]TBPS binding. For compounds 1c and 1d, a discrepanc y between GABA ratio and [S-35]TBPS binding data was observed. Only th e latter assay was in full agreement with the pharmacological data, wh ich indicated an inverse agonist and a partial agonist profile for 2k, q and 1c,d respectively. The affinity and intrinsic activity data of c ompounds 1c,d and 2j,k,q are discussed in the light of the recently pr oposed pharmacophore model by Skolnick/Cook; in particular, the agonis tic activity of 1c,d is interpreted on the basis of a possible interac tion 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 beta-CCE.