Design, synthesis and binding affinity of new nicotinic ligands

Nicotinic ligands can be potentially useful as drugs for the management of several important pathologies as well as pharmacological tools to characterize nicotinic receptor subtypes. The design of new nicotinic ligands has been carried out by applying the 3D database search method; thus, the Cambridge Structural Database has been scanned with a query consisting in a pharmacophore substructure with 3D constraints. The nicotinic pharmacophoric features have been obtained from the structure of pyrido[3,4-b] homotropane (PHT), which represents a rigid template. The results of the query suggested the aminoalkylquinoline moiety as simple scaffold, and it was further refined using molecular modeling. Some of the synthesized compounds were found to interact with the central nicotinic receptor on rat cerebral cortex, showing affinity in the nanomolar range and displaying analgesic properties. The possible binding mode of these substances with a homology-built model of the nicotinic receptor has been analyzed by means of induced fit studies.