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ARS Home » Pacific West Area » Logan, Utah » Poisonous Plant Research » Research » Publications at this Location » Publication #354964
Title: Absolute configuration and pharmacology of the poison frog alkaloid phantasmidine

Author
item FITCH, RICHARD - Indiana State University
item SNIDER, BARRY - Brandeis University
item ZHOU, QUAN - Brandeis University
item FOXMAN, BRUCE - Brandeis University
item PANDYA, ANSHUL - National Institute Of Environmental Health Sciences (NIEHS, NIH)
item YAKEL, JERREL - National Institute Of Environmental Health Sciences (NIEHS, NIH)
item OLSON, THAO - Georgetown University
item AL-MUHTASIB, NOUR - Georgetown University
item XIAO, YINGXIAN - Georgetown University
item Welch, Kevin
item Panter, Kip

Submitted to: Journal of Natural Products
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/6/2018
Publication Date: 4/19/2018
Citation: Fitch, R.W., Snider, B.B., Zhou, Q., Foxman, B.M., Pandya, A.A., Yakel, J.L., Olson, T., Al-Muhtasib, N., Xiao, Y., Welch, K.D., Panter, K.E. 2018. Absolute configuration and pharmacology of the poison frog alkaloid phantasmidine. Journal of Natural Products. 81(4):1029-1035. https://doi.org/10.1021/acs.jnatprod.8b00062.
DOI: https://doi.org/10.1021/acs.jnatprod.8b00062

Interpretive Summary: Phantasmidine, a structural analog of epibatidine, is a highly potent nicotinic acetylcholine receptor (nAChR) agonist found in the poison frog (Epipedobates anthonyi). Natural phantasmidine is not a single enantiomer, but an approximately 4:1 mixture. Structurally and pharmacologically distinct from epibatidine, phantasmidine is a potent and selective partial agonist for a4ß2 nAChR. Pharmacological characterization established that phantasmidine is ~10-fold less potent than epibatidine, but ~100-fold more potent than nicotine in most receptors tested. While phantasmidine itself is too toxic for direct therapeutic use, we believe it is a useful platform for the development of potent and selective nicotinic agonists, which may have value as pharmacological tools.

Technical Abstract: Phantasmidine, a rigid congener of the well-known nicotinic acetylcholine receptor agonist epibatidine, is found in the same species of poison frog ( Epipedobates anthonyi). Natural phantasmidine was found to be a 4:1 scalemic mixture, enriched in the (2a R,4a S,9a S) enantiomer by chiral-phase LC-MS comparison to the synthetic enantiomers whose absolute configurations were previously established by Mosher's amide analysis. The major enantiomer has the opposite S configuration at the benzylic carbon to natural epibatidine, whose benzylic carbon is R. Pharmacological characterization of the synthetic racemate and separated enantiomers established that phantasmidine is ~10-fold less potent than epibatidine, but ~100-fold more potent than nicotine in most receptors tested. Unlike epibatidine, phantasmidine is sharply enantioselective in its activity and the major natural enantiomer whose benzylic carbon has the 4a S configuration is more active. 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. While phantasmidine itself is too toxic for direct therapeutic use, we believe it is a useful platform for the development of potent and selective nicotinic agonists, which may have value as pharmacological tools.