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 [3H]-epibatidine and [125I]-alfa-bungarotoxin from the most widespread brain nAChRs subtypes alfa4beta2 and alfa7, respectively. While the affinity for alfa7 subtype was rather poor (Ki from 0.4 to >50 μM), the affinity for alfa4beta2 subtype was very interesting, with nanomolar Ki values for the best compounds. The N-substituted cytisines were docked into the rat and human alfa4beta2 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 aminoacid residues of the alfa and beta subunits essential for the ligand binding on rat and human nAChRs, providing a novel structural framework for the development of new alfa4beta2 selective ligands.

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

TASSO, BRUNO;SPARATORE, FABIO
2009

Abstract

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 [3H]-epibatidine and [125I]-alfa-bungarotoxin from the most widespread brain nAChRs subtypes alfa4beta2 and alfa7, respectively. While the affinity for alfa7 subtype was rather poor (Ki from 0.4 to >50 μM), the affinity for alfa4beta2 subtype was very interesting, with nanomolar Ki values for the best compounds. The N-substituted cytisines were docked into the rat and human alfa4beta2 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 aminoacid residues of the alfa and beta subunits essential for the ligand binding on rat and human nAChRs, providing a novel structural framework for the development of new alfa4beta2 selective ligands.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11567/226776
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