Synthesis and Evaluation of Nicotine Analogs as Neuronal Nicotinic Acetylcholine Receptor Ligands

Abstract

A series of 3'-, 4'-, and 5'-substituted nicotine analogs have been synthesized and evaluated as ligands of the neuronal nicotinic acetylcholine receptor. The compounds prepared were found to have binding affinities ranging from 4 to 3500 nM. The results indicate that only a small substituent or functionality is well tolerated at the C4' position of nicotine and that binding affinity is affected by both steric and electronic properties of the substituent. On the other hand, the C3' and C5' positions seem to be the more sensitive toward bulky substituents. The best compound, 4'-methylnicotine, is nearly equipotent to nicotine. It possesses the most favorable binding affinity.

Structure-activity relationships for nicotine analogs comparing competition for [3H]nicotine binding and psychotropic potency

“…Recently, a number of structure-activity studies have appeared relating chemical structure to both receptor binding affinity, employing [ logical potency. Among the nicotine analogs studied were 3′-, 4′-, and 5′- [Lin et al, 1994] substituted, N′-substituted [Abood et al, 1993;Glassco et al, 1996], pyrrolidine modified and 6-substituted [Dukat et al, 1996], and 3-pyridyl ethers with subnanomolar affinities for nicotinic cholinergic receptors [Abreo et al, 1996].…”

Benzotriazole-Mediated Synthesis of Nitrogen-Containing Heterocycles

“…Pyrrolidinones possess varied biological activities and have been used as pharmaceuticals [66][67][68][69]. They can also be intermediates in the synthesis of pyrrolidine alkaloids and γ-amino acids [70][71][72][73][74].…”

Nicotinic Agonists, Antagonists, and Modulators From Natural Sources

“…Among analogs with substituents on the pyrrolidine ring, only 4 -methylnicotine retained modest affinity for α 4 β 2 receptors (Lin et al, 1994;Kim et al, 1996). Two analogs in Fig.…”