Pyrrolo[2,3-h]tetrahydroisoquinoline Derivatives Exhibiting Mixed Dopaminergic D3 > D2 and Serotoninergic 5-HT6 Affinity

Abstract A series of pyrrolo[2,3-h]tetrahydroisoquinoline derivatives has been synthesized and shown to be potent ligands at the 5-HT6, D2, and D3 receptors. By systematically changing the structural elements, we have arrived at (+)-2-{7-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-2-methyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h]isoquinolin-3-yl}ethanol [(+)-6Ab], a compound exhibiting the targeted receptor profile, considered to be potentially effective for the treatment of neurodegenerative disorders related to schizophrenia. In the course of the elaboration of the synthetic routes, several new tetrahydroisoquinoline derivatives as versatile synthetic building blocks have been prepared.