A new agonist, isoarecolone methiodide (1,1-dimethyl-4-acetyl-1,2,3,6-tetrahydropyridinium iodide) was tested at the frog neuromuscular junction. It was 50 times more potent than carbamylcholine, making it one of the most potent nicotinic agonists known. In addition, its cyclic structure and conjugated carbonyl bond endow it with near rigidity. An analogous compound, 1,1-dimethyl-4-acetylpiperazinium iodide, was synthesized because of its similar geometry and rigidity. It was 2.6 times as potent as carbamylcholine but only 0.053 times as potent as isoarecolone methiodide. Computer assisted molecular modeling and molecular orbital calculations revealed steric and electrostatic field differences between these two compounds.