INHIBITION OF NICOTINE RECEPTORS BY TETRAPONERINE ANTALKALOIDS.

William R. Kem, Vladimir M. Mahnir, Raja Ma’an and Jean-Claude Braekman.
Dept. of Pharmacology and Therapeutics, University of Florida, Gainesville,FL 32610, USA.
Laboratory of Bio-organic Chemistry, Faculty of Sciences, Universityof Brussels, 1050 Brussels, Belgium.

The tetraponerines are a group of alkaloids occurring in venom of aNew Guinean ant, Tetraponera sp. (Braekman et al, 1987, Z. Naturforsch.42C, 627). Several compounds have been isolated and their structures elucidated(Merlin et al., 1988, J. Chem Ecol, 14, 517). Although these compoundswere reported to possess insecticidal activity, their mechanisms of actionhad not been previously investigated. We have studied the actions of severaltetraponerines upon frog skeletal muscle and rat brain nicotinic receptorsand obtained evidence that they act as non-competitive antagonists on thesecholinergic receptors. The relative potencies of the tetraponerines inblocking the contractile response of frog skeletal muscle to a stable cholinergicagonist (carbamylcholine) were T-7>T-8>T-4. These results indicate thatincreasing the size of the alkyl substitute at C-9 increases potency. Consistentwith this trend, removal of the C-9 alkyl substituent greatly reduced neuromuscularblocking potency. The configuration at C-5 affected potency much more thanthe C-9 configuration. T-7 failed to affect the binding of 3H-cytisineto high nicotine affinity rat brain nicotinic receptors, which suggeststhat the tetraponerines act at a site on nicotinic receptors differentfrom the ACh recognition site, probably within the ion channel.