New substituted 2-methylthiomethyl- and 2-methylsulphinylmethylenebenzimidazoles with D2/5-HT1A activity

Several 2-methylthiomethylbenzimidazoles (3a-e) and the corresponding sulphinyl derivatives 4a-e were synthesized and evaluated measuring their in vitro binding affinity at the D-1 and D-2 dopamine (source: synaptosomal membranes of the bovine nucleus caudatus) and 5-HT1A serotonin (source: synaptosomal membranes of the bovine hippocampus) receptors. [H-3]SCH 23390, [H-3]piperone, and [H-3]-8-OH-DP4T were employed as specific radioligands for the D-1, D-2 and 5-HT1A receptors, respectively. None of the compounds except for 3b acting as a moderate [H-3]SCH 23390, competitor, expressed binding affinity at the D-1 receptor. Compounds 4a and 4e were inactive displacers of both [H-3]spiperone and [H-3]-8-OH-DPAT. Ligands 4b, 3d and 4d acted as weak to moderate [H-3]spiperone competitors and 3a was a weak [H-3]-8-OH-DPAT displacer. The remaining ligands expressed binding affinity at the corresponding receptors in a nanomolar concentration range. Among them, compound 3b with K-i of 14.2 nM and 8.4 nM in [H-3]spiperone and [H-3]-8-OH-DPAT binding assay, respectively, was the most potent mixed dopaminergic/serotonergic ligand. Although sterically similar, the two classes of ligands differ with regard to electronic properties of substituents in position 2 of the benzimidazole ring. Oxidation of 2-(methylthiomethyl)benzimidazoles afforded ligands devoid of binding affinity at the 5-HT1A receptor and significantly reduced binding affinity at the D-2 receptor. This points to the importance of electronic properties of substituents in position 2 of benzimidazole ring for the D-2/5-HT1A affinity ratio of this type of ligands.