3-(5-Alkylamino-4-isoxazolyl)-1,2,5,6-tetrahydropyridines: a novel class of central nicotinic receptor ligands Original Research Article

A novel class of central nicotinic acetylcholine receptor ligands, 3-(5-alkylamino-4-isoxazolyl)-1,2,5,6-tetrahydropyridine 4a–f, was synthesized. Several of the compounds showed high affinity for central nicotinic receptors (4c: IC50=50 nM), with more than a 100-fold selectivity for nicotinic over muscarinic receptors. The compounds showed up to a 10-fold selectivity for the central nicotinic subtype combination α4β2 (4c: IC50=4.6 nM), as compared to the major ganglionic subtype composed of α3 containing subunits (4c: IC50=48 nM). The compounds were further evaluated in a dopamine release assay in vitro, and in a drug discrimination assay in vivo. Compound 4a is an effective nicotinic agonist with a potency 50–100 times lower than nicotine. Extending the alkylamino chain beyond one, compound (4b–f), changed the pharmacological profile of the compounds in an antagonistic direction.