(±)-Octahydro-2-methy 1-trans-5 (1H)-isoquinolone methiodide: A probe that reveals a partial map of the nicotinic receptor's recognition site

A new, semirigid, nicotinic agonist ( ± )-octahydro-2-methyl-trans-5 (1H)-isoquinolone methiodide was synthesized. The disposition of this agonist's nitrogen and carbonyl group conforms well to the prevailing notion of a pharmacophore for the nicotinic receptor. Comparing its structure and electrostatic potential surfaces, we predicted that its activity would be similar to that of carbamylcholine at the frog neuromuscular junction. Instead, the potency of the isoquinolone was only 0.015 times as potent as (+) carbamylcholine. We conclude, after eliminating other possibilities, that the vicinity of the carbonyl group of an agonist must be planar to fit a confined space within the receptor's recognition site. The isoquinolone is a weak agonist because its methylene group β to the carbonyl intrudes on this space.