ANABASEINE IS A POTENT AGONIST ON MUSCLE AND NEURONAL ALPHA-BUNGAROTOXIN-SENSITIVE NICOTINIC RECEPTORS

We assessed the pharmacological activity of anabaseine, a toxin found in certain animal venoms, relative to nicotine and anabasine on a vari ety of vertebrate nicotinic receptors, using cultured cells, the Xenop us oocyte expression system, contractility assays with skeletal and sm ooth muscle strips containing nicotinic receptors and in vivo rat pros tration assay involving direct injection into the lateral ventricle of the brain. Anabaseine stimulated every subtype of nicotinic receptor that was tested. It was the most potent frog skeletal muscle nicotinic receptor agonist. At higher concentrations it also blocked the BC(3)H 1 (adult mouse) muscle type receptor ion channel. The affinities of th e three nicotinoid compounds for rat brain membrane alpha-bungarotoxin binding sites and their potencies for stimulating Xenopus oocyte homo meric alpha7 receptors, expressed in terms of their active monocation concentrations, displayed the same rank order, anabaseine>anabasine>ni cotine. Although the maximum currents generated by anabaseine and anab asine at alpha7 receptors were equivalent to that of acetylcholine, th e maximum response to nicotine was only about 65% of the acetylcholine response. At alpha4-beta2 receptors the affinities and apparent effic acies of anabaseine and anabasine were much less than that of nicotine . Anabaseine, nicotine and anabasine were nearly equipotent on sympath etic (PC12) receptors, although parasympathetic (myenteric plexus) rec eptors were much more sensitive to anabaseine and nicotine but less se nsitive to anabasine. These differences suggest that there may be diff erent subunit combinations in these two autonomic nicotinic receptors. The preferential interactions of anabaseine, anabasine and nicotine w ith different receptor subtypes provides molecular clues that should b e helpful in the design of selective nicotinic agonists.