Nicotinic acetylcholine receptors (nAChRs) are the subject of ever increasing interest because of their presumed involvement in the etiology of numerous clinical disorders. Unfortunately, the absence of atomic-level structural data, as well as the pharmacological complexity of these receptors leaves many fundamental questions unanswered. An understanding of how ligands interact with the receptor and, in-turn, how these interactions lead to pharmacological effect is vital in the advancement of nAChR-based therapeutics. We will first explore physico-chemical themes that are evidenced to be of particular importance in nAChR molecular recognition; these are- p-cation interaction, conformational entropy and stereochemistry. The second objective of this review is an interpretive encapsulation of the extensive and disparate body of structure-activity data that now exists for nAChRs. Finally, this review will advocate a re-investigation of distance geometry based methods as well as the need for additional approaches in nicotinic receptor pharmacophore generation.
Keywords: molecular recognition, nicotinic, acettkcgikube receptors, nAChRs, etiology, clinical disorders, nAChR based therapeutics, cation interaction, conformational entropy, stereochemistry, neurotransmitters, NT receptors, ligand gated ion channel, GABAA, 5HT3, NMDA AMPA kinate, mrmbrane spanning regions, subtype, receptor kinetics, allosterism, centrald nervous system CNS, receptor structure, neuromusculllar Torpedo receptors, stoichiometry, nAChR diversity, HAB site, receptor desensitization, protonation induced chirality, nicotinic ligands, azabicyclic analogs, high affinity binding, hydrogen bond acceptor, electoron containing moiety, methylcarbamylcholine, nicotine, 3 pyridylmethylcholine receptor, peripheral nervous system, structure activitiy, affinity relationship
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Published on: 01 March, 2012
Page: [749 - 800]