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

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 ove...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 1998-09, Vol.6 (9), p.1623-1629
Main Authors: Olesen, P H, Swedberg, M D, Rimvall, K
Format: Article
Language:English
Subjects:
Animals
Cerebral Cortex - metabolism
In Vitro Techniques
Ligands
Magnetic Resonance Spectroscopy
Male
Mass Spectrometry
Pyridines - metabolism
Rats
Rats, Wistar
Receptors, Nicotinic - metabolism
Spodoptera
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Summary: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.
ISSN:0968-0896
DOI:10.1016/S0968-0896(98)00101-1