Selectivity of Spiroimine Phycotoxins Toward Nicotinic Acetylcholine Receptors

Abstract

Spiroimine phycotoxins are macrocyclic marine neurotoxins that are found in contaminated shellfish [1,2]. Most of them are strong antagonists of nicotinic acetylcholine receptors (nAChRs), with high affinity and selectivity on different subtypes [3].In this study, we used different ligand- and structure-based molecular modeling methods to identify the residues that are controlling the affinity and the selectivity of representative members of this toxins family toward different subtypes of nAChRs. The conformation flexibility of the macrocyclic ring was an essential requirement for the correct positioning of ligands in the binding site [4,5]. The pertinence of different approaches to generate macrocyclic ring conformers will be discussed.Our results will guide further structural modifications within this spiroimine phycotoxins family, to design a new generation of synthetic derivatives with better activity and selectivity profiles.1. Molgo et al. “Cyclic imine toxins: chemistry, origin, metabolism, pharmacology, toxicology, and detection” in “Seafood and freshwater toxins. Pharmacology physiology and detection”, CRC Press, 2014, pp 951-990.2. Molgo et al. “Cyclic imine neurotoxins acting on muscarinic and nicotinic acetylcholine receptors” in “Toxins and biologically active compounds from microalgae”, CRC Press, 2014, pp 116-146.3. Molgo et al., Exp. Opin. Drug Discov. 2013, 8, 1203.4. Araoz et al., J. Am. Chem. Soc. 2011, 133, 10499-10511.5. Araoz et al., Toxicol. Sci. 2015, 147, 156-167.