Exploring the Nature of Molecular Recognition in Nicotinic Acetylcholine Receptors

Abstract

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- pi-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.

Design, Synthesis, and Preliminary Pharmacological Evaluation of New Quinoline Derivatives as Nicotinic Ligands

“…16 On these bases, we thought it interesting to continue our work in two directions: to study the enantioselectivity of compounds 1b and 1c and to test a new series of quinolinyl derivatives, characterized by a pharmacophoric N-N distance greater than 6.6 Å. Compounds 2-4 were therefore designed (Chart 1), which represent the product of hybridization between quinoline and the basic portion of high affinity nicotinic ligands such as A-84543, 15 N-methyl-3-(4-aminobutynyl)pyridine, 17,18 or transmetanicotine. Moreover, we decided to also test the cisderivative 5 and the analogues with a 3-C-atoms side chain (compounds 6-8).…”

Synthesis and evaluation of conformationally restricted pyridino N‐alkylated nicotine analogs as nicotinic acetylcholine receptor antagonists

“…Recent research in drug discovery has focused primarily on the development of novel nicotinic receptor agonists [Holladay et al, 1997;Glennon and Dukat, 2000;Lloyd and Williams, 2000;Tonder and Olesen, 2001;Schmitt, 2000;Lin and Meyer, 1998]. However, considerably less effort has been directed at the development of subtype-selective nAChR antagonists, even though only a limited number of nAChR antagonists currently exist.…”

Nicotinic Agonists, Antagonists, and Modulators From Natural Sources

“…Another furopyridyl analog with a azabicylic indolizidine ring has a slightly higher affinity (K i 0.39 nM) for α 4 β 2 receptors . A similar furopyridyl analog of epibatidine (K i 0.86 nM at α 4 β 2 receptors) has been reported (Schmidt, 2000). A conformationally constrained pyridyl ether SSR591813 recently was reported to be a partial α 4 β 2 selective agonist with potential for smoking cessation (Cohen et al, 2003).…”

“…Carbamylcholine itself is somewhat selective for muscarinic receptors. Comprehensive reviews of muscarinic agents (Moltzen and Bjornholm, 1995;Caulfield and Birdsall, 1998;Felder et al, 2000;Bikádi and Simonyi, 2003;Bunnelle et al, 2004) and of nicotinic agents (Glennon and Dukat, 2000;Schmidt, 2000;Tønder and Olesen, 2001;Bunnelle and Decker, 2003;Romanelli and Gualtieri, 2003) are available. The present review intends to highlight natural products and some representative synthetics with emphasis on nicotinic agonists.…”