6,6-Spiroimine analogs of (-)-gymnodimine A: synthesis and biological evaluation on nicotinic acetylcholine receptors.
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.
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, Gif-sur-Yvette, France.
Leslie
L
Duroure
Thierry
T
Jousseaume
Rómulo
R
Aráoz
Elvina
E
Barré
Pascal
P
Retailleau
Laurent
L
Chabaud
Jordi
J
Molgó
Catherine
C
Guillou
D000818:Animals; D055724:Electrophysiological Phenomena / Q000187:drug effects; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007097:Imines / Q000138:chemical synthesis* / Q000494:pharmacology; D008024:Ligands; D015394:Molecular Structure; D018733:Nicotinic Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D014982:Xenopus laevis
D006576:Heterocyclic Compounds, 4 or More Rings; D007097:Imines; D008024:Ligands; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D013141:Spiro Compounds; C569130:gymnodimine A