title: Semisynthetic analogues of toxiferine I and their pharmacological properties at α7 nAChRs, muscle-type nAChRs, and the allosteric binding site of muscarinic M2 receptors.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Chemistry, The German University in Cairo , New Cairo City, 11835 Cairo, Egypt.
authors.forename: Darius P
authors.initials: DP
authors.lastname: Zlotos
authors.forename: Christian
authors.initials: C
authors.lastname: Tränkle
authors.forename: Ulrike
authors.initials: U
authors.lastname: Holzgrabe
authors.forename: Daniela
authors.initials: D
authors.lastname: Gündisch
authors.forename: Anders A
authors.initials: AA
authors.lastname: Jensen
mesh_terms: D000470:Alkaloids / Q000737:chemistry; D000495:Allosteric Site; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D009132:Muscles / Q000378:metabolism; D018733:Nicotinic Antagonists / Q000494:pharmacology; D019906:Nuclear Magnetic Resonance, Biomolecular; D043585:Receptor, Muscarinic M2 / Q000737:chemistry*; D014117:Toxiferine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000737:chemistry*
chemical_list: D000470:Alkaloids; D008024:Ligands; D018733:Nicotinic Antagonists; D043585:Receptor, Muscarinic M2; D064569:alpha7 Nicotinic Acetylcholine Receptor; D014117:Toxiferine