Abstract

Synthetic (+)- and (-)-epibatidine (an alkaloid originally characterized from frog skin) have potent analgetic activity in mice, using the hot-plate assay. The natural (+)-enantiomer, with an ED50 of about 1.5 micrograms/kg upon intraperitoneal injection, is about 2-fold more potent than the (-)-enantiomer. The analgetic activity is blocked by the nicotinic antagonist mecamylamine. Both the (+)- and (-)-enantiomers have high affinity (Ki values of 0.045 and 0.058 nm, respectively) for nicotinic sites that bind [3H] nicotine in rat brain membranes. An analog of epibatidine with the chloro substituent of the pyridyl ring replaced with hydrogen has comparable affinity for nicotinic sites, whereas replacement with a methyl or iodo substituent lowers activity. Both (+)- and (-)-epibatidine have potent agonist activity at ganglionic-type nicotinic receptors in pheochromocytoma PC-12 cells, with EC50 values for stimulation of sodium influx of 72 and 111 nM, respectively. (-)-Epibatidine is about 5-fold less potent as an agonist at muscle-type central nicotinic receptors of medulloblastoma TE671 cells. It would appear that the analgetic activity of epibatidine is due to activity as a nicotinic agonist. The epibatidines have little or no activity at a variety of other central receptors, including opioid receptors, muscarinic receptors, adrenergic receptors, dopamine receptors, serotonin receptors, and gamma-aminobutyric acid receptors.