title: 3-(5-Alkylamino-4-isoxazolyl)-1,2,5,6-tetrahydropyridines: a novel class of central nicotinic receptor ligands.
abstract: 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 alpha 4 beta 2 (4c: IC50 = 4.6 nM), as compared to the major ganglionic subtype composed of alpha 3 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.
authors.affiliation: Novo Nordisk, Måløv, Denmark. phol@novo.dk
authors.forename: P H
authors.initials: PH
authors.lastname: Olesen
authors.forename: M D
authors.initials: MD
authors.lastname: Swedberg
authors.forename: K
authors.initials: K
authors.lastname: Rimvall
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D066298:In Vitro Techniques; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D011725:Pyridines / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000378:metabolism*; D018411:Spodoptera
chemical_list: D008024:Ligands; D011725:Pyridines; D011978:Receptors, Nicotinic