Absolute Configuration and Pharmacology of the Poison Frog Alkaloid Phantasmidine

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 (2aR,4aS,9aS) 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 4aS 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.