6,6-Spiroimine analogs of (-)-gymnodimine A: synthesis and biological evaluation on nicotinic acetylcholine receptors
| Autor: | Pascal Retailleau, Rómulo Aráoz, Leslie Duroure, Laurent Chabaud, Catherine Guillou, Thierry Jousseaume, Elvina Barre, Jordi Molgó |
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| Přispěvatelé: | Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Institut de Neurobiologie Alfred Fessard (INAF), Neurobiologie & Développement (N&D) |
| Rok vydání: | 2011 |
| Předmět: |
Stereochemistry
Xenopus Nicotinic Antagonists Receptors Nicotinic 010402 general chemistry Ligands 01 natural sciences Biochemistry Heterocyclic Compounds 4 or More Rings chemistry.chemical_compound Xenopus laevis Moiety Animals Humans Spiro Compounds Physical and Theoretical Chemistry ComputingMilieux_MISCELLANEOUS Acetylcholine receptor biology Molecular Structure 010405 organic chemistry [CHIM.ORGA]Chemical Sciences/Organic chemistry Organic Chemistry Acrolein Enantioselective synthesis Stereoisomerism biology.organism_classification 0104 chemical sciences 3. Good health Electrophysiological Phenomena Nicotinic agonist chemistry Michael reaction [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] Female Imines Pharmacophore |
| Zdroj: | Organic and Biomolecular Chemistry Organic and Biomolecular Chemistry, Royal Society of Chemistry, 2011, 9, pp.8112-8118. ⟨10.1039/c1ob06257c⟩ Organic and Biomolecular Chemistry, Royal Society of Chemistry, 2011, 9 (23), pp.8112-8. ⟨10.1039/c1ob06257c⟩ |
| ISSN: | 1477-0539 1477-0520 |
| DOI: | 10.1039/c1ob06257c⟩ |
| Popis: | International audience; Simple models of the spiroimine core of (-)-gymnodimine A have been synthesized in racemic and optically active forms. The quaternary carbon of the racemic spiroimines was created by Michael addition of a β-ketoester to acrolein, whereas the asymmetric allylic alkylation of the same β-ketoester was used to access the spiroimines in an enantioselective fashion. Both racemic and enantio-enriched mixtures were tested for their biological activities on Xenopus oocytes either expressing (human α4β2) or having incorporated (Torpedoα1(2)βγδ) nicotinic acetylcholine receptors (nAChRs). These spiroimine analogs of (-)-gymnodimine A inhibited acetylcholine-evoked nicotinic currents, but were less active than the phycotoxin. Our results reveal that the 6,6-spiroimine moiety is important for the blockade of nAChRs and support the hypothesis that it is one of the pharmacophores of this group of toxins. |
| Databáze: | OpenAIRE |
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