The interactions of eighteen natural and synthetic gephyrotoxin and indolizidine alkaloids with binding sites on nicotinic acetylcholine receptor channel (AChR) complex from Torpedo californica electric organ were investigated using two radiolabeled probes, [3H]perhydrohistrionicotoxin and [3H]phencyclidine. Both gephyrotoxins and indolizidines were moderately active inhibitors of the binding of these probes (Ki's = 0.1-20 microM), but did not interact with the acetylcholine binding site. Structure-activity relationships indicate an important contribution of hydrophobic interactions to both gephyrotoxin and indolizidine binding. The stereoconfiguration of the alkaloids had little effect on binding. Carbamylcholine enhanced the affinity of certain alkaloids up to 6 to 8-fold suggesting that interactions with open or desensitized conformations of the AChR complex are favored over interactions with resting conformations.