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

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摘要：

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.

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关键词：

3-(5-Alkylamino-4-isoxazolyl)-1,2,5,6-tetrahydropy agonist antagonist cholinergic channel modulators functional activity nicotinic subtype selectivity

DOI：

10.1016/S0968-0896(98)00101-1

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年份：

1998