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 D1 and D2 dopamine (source: synaptosomal membranes of the bovine nucleus caudatus) and 5-HT1A serotonin (source: synaptosomal membranes of the bovine hippocampus) receptors. [3H]SCH 23390, [3H]spiperone, and [3H]-8-OH-DPAT were employed as specific radioligands for the D1, D2 and 5-HT1A receptors, respectively. None of the compounds except for 3b acting as a moderate [3H]SCH 23390, competitor, expressed binding affinity at the D1 receptor. Compounds 4a and 4e were inactive displacers of both [3H]spiperone and [3H]-8-OH-DPAT. Ligands 4b, 3d and 4d acted as weak to moderate [3H]spiperone competitors and 3a was a weak [3H]-8-OH-DPAT displacer. The remaining ligands expressed binding affinity at the corresponding receptors in a nanomolar concentration range. Among them, compound 3b with Ki of 14.2 nM and 8.4 nM in [3H]spiperone and [3H]-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 D2 receptor. This points to the importance of electronic properties of substituents in position 2 of benzimidazole ring for the D2/5-HT1A affinity ratio of this type of ligands.
Institute of Chemistry, Technology and Metallurgy, Belgrade, Serbia, Yugoslavia.
S
S
Kostić-Rajacić
V
V
Soskić
J
J
Joksimović
D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D002417:Cattle; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism; D015259:Dopamine Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008024:Ligands; D017447:Receptors, Dopamine D1 / Q000187:drug effects; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D018490:Serotonin Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D013441:Sulfinic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D013574:Synaptosomes / Q000378:metabolism
D001562:Benzimidazoles; D015259:Dopamine Agents; D008024:Ligands; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D018490:Serotonin Agents; D013441:Sulfinic Acids