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A new series of analogues of the calabash curare alkaloid toxiferine I was prepared and pharmacologically evaluated at α7 and muscle-type nAChRs and the allosteric site of muscarinic M2 receptors. The new ligands differ from toxiferine I by the absence of one (2a-c) or two (3a-c) hydroxy groups, saturation of the exocyclic double bonds, and various N-substituents (methyl, allyl, 4-nitrobenzyl). At the muscle-type nAChRs, most ligands showed similar binding to the muscle relaxant alcuronium, indicating neuromuscular blocking activity, with the nonhydroxylated analogues 3b (Ki = 75 nM) and 3c (Ki = 82 nM) displaying the highest affinity. At α7 nAChRs, all ligands showed a moderate to low antagonistic effect, suggesting that the alcoholic functions are not necessary for antagonistic action. Compound 3c exerted the highest preference for the muscle-type nAChRs (Ki = 82 nM) over α7 (IC50 = 21 μM). As for the allosteric site of M2 receptors, binding was found to be dependent on N-substitution rather than on the nature of the side chains. The most potent ligands were the N-allyl analogues 2b and 3b (EC0.5,diss = 12 and 36 nM) and the N-nitrobenzyl derivatives 2c and 3c (EC0.5,diss = 32 and 49 nM). The present findings should help delineate the structural requirements for activity at different types of AChRs and for the design of novel selective ligands.

journal of natural products

Semisynthetic Analogues of Toxiferine I and Their Pharmacological Properties at α7 nAChRs, Muscle-Type nAChRs, and the Allosteric Binding Site of Muscarinic M<sub>2</sub> Receptors

Semisynthetic Analogues of Toxiferine I and Their Pharmacological Properties at α7 nAChRs, Muscle-Type nAChRs, and the Allosteric Binding Site of Muscarinic M2 Receptors

Semisynthetic Analogues of Toxiferine I and Their Pharmacological Properties at α7 nAChRs, Muscle-Type nAChRs, and the Allosteric Binding Site of Muscarinic M₂ Receptors