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  • Synthesis, binding, and modeling studies of new cytisine derivatives, as ligands for neuronal nicotinic acetylcholine receptor subtypes.

Synthesis, binding, and modeling studies of new cytisine derivatives, as ligands for neuronal nicotinic acetylcholine receptor subtypes.

Journal of medicinal chemistry (2009-06-25)
Bruno Tasso, Caterina Canu Boido, Emanuela Terranova, Cecilia Gotti, Loredana Riganti, Francesco Clementi, Roberto Artali, Gabriella Bombieri, Fiorella Meneghetti, Fabio Sparatore
RESUMO

The availability of drug affecting neuronal nicotinic acetylcholine receptors (nAChRs) may have important therapeutic potential for the treatment of several CNS pathologies. Pursuing our efforts on the systematic structural modification of cytisine and N-arylalkyl and N-aroylalkyl cytisines were synthesized and tested for the displacement of [(3)H]-epibatidine and [(125)I]-alpha-bungarotoxin from the most widespread brain nAChRs subtypes alpha(4)beta(2) and alpha(7), respectively. While the affinity for alpha(7) subtype was rather poor (K(i) from 0.4 to >50 microM), the affinity for alpha(4)beta(2) subtype was very interesting, with nanomolar K(i) values for the best compounds. The N-substituted cytisines were docked into the rat and human alpha(4)beta(2) nAChR models based on the extracellular domain of a molluscan acetylcholine binding protein. The docking results agreed with the binding data, allowing the detection of discrete amino acid residues of the alpha and beta subunits essential for the ligand binding on rat and human nAChRs, providing a novel structural framework for the development of new alpha(4)beta(2) selective ligands.

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Cytisine, ≥99%, powder

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