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Phantasmidine, a Rigid Epibatidine Congener, Is a Potent, Stereoselective and Subtype‐Selective Agonist at Nicotinic Acetylcholine Receptors
Author(s) -
Fitch Richard W.,
Pandya Anshul A.,
Yakel Jerrel L.,
Olson Thao T.,
AlMuhtasib Nour,
Xiao Yingxian,
Welch Kevin D.,
Panter Kip E.,
Zhou Quan,
Snider Barry B.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb596
Subject(s) - epibatidine , chemistry , stereochemistry , agonist , stereoselectivity , nicotinic agonist , acetylcholine receptor , receptor , pharmacology , partial agonist , enantiomer , nicotinic acetylcholine receptor , biochemistry , biology , catalysis
Phantasmidine is a rigid congener of the well‐known nicotinic receptor agonist epibatidine and is found in the same species of poison frog ( Epipedobates anthonyi ). It is a condensed tetracyclic alkaloid containing pyridine, furan, pyrrolidine, and cyclobutane rings fused in sequence. Racemic phantasmidine is ~ 10‐fold less potent than epibatidine in all receptors tested, but ~100‐fold more potent than nicotine. Unlike epibatidine, phantasmidine is sharply enantioselective in its activity. In all cases, the eutomer was that having the (2a R ,4a S ,9a S ) configuration. Eudismic ratios from radioligand binding in transfected cells and rat cortex varied between 30 and 45, while those from functional assays ranged more widely and were subtype‐dependent. Function was measured using electrophysiology and 86 Rb efflux. The lowest eudismic ratio found was for α7 receptors (~5) while the highest was for central α3β4 receptors (~480). The stereoselective pharmacology of phantasmidine is ascribed to its rigid and asymmetric shape as compared to the nearly symmetric conformations previously suggested for epibatidine enantiomers. Given the rigidity and enantioselectivity of phantasmidine, it has significant potential as a lead for the development of selective nicotinic agonists. Support or Funding Information This work was supported in part by grants from the National Science Foundation (RUI, CHE1012629, MRI CHE1531972 and CCLI‐DUE0942345), National Institutes of Health (R21GM07278001A1, R21DA032489, U19DA027990), by the Intramural Research Program of National Institute of Environmental Health Sciences (NIEHS/NIH), and funds from the Department of Chemistry and Physics at Indiana State University.