Identification and pharmacological profile of a new class of selective nicotinic acetylcholine receptor potentiators.

Here we report the discovery, by high-throughput screening, of three novel (2-amino-5-keto)thiazole compounds that act as selective potentiators of nicotinic acetylcholine receptors. Compound selectivity was assessed at seven human nicotinic acetylcholine receptors (alpha1beta1gammadelta, alpha2beta4, alpha3beta2, alpha3beta4, alpha4beta2, alpha4beta4, and alpha7) expressed in mammalian cells or Xenopus oocytes. At alpha2beta4, alpha4beta2, alpha4beta4, and alpha7, but not alpha1beta1gammadelta, alpha3beta2, or alpha3beta4, submaximal responses to nicotinic agonists were potentiated in a concentration-dependent manner by all compounds.

Stable expression and characterisation of a human alpha 7 nicotinic subunit chimera: a tool for functional high-throughput screening.

A chimera comprising the N-terminal region of the human alpha7 nicotinic acetylcholine receptor, fused to the transmembrane/C-terminal domains of the mouse serotonin 5-HT3 receptor, was constructed. Injection of the chimera cDNA into Xenopus oocytes, or transient transfection in human embryonic kidney (HEK-293) cells, resulted in the expression of functional channels that were sensitive to nicotinic acetylcholine, but not serotonin receptor ligands. In both systems, the responses obtained from chimeric receptors inactivated more slowly than those recorded following activation of wild-type alpha7 receptors.

Expression and functional characterisation of a human chimeric nicotinic receptor with alpha6beta4 properties.

Despite being cloned several years ago, the expression of functional nicotinic acetylcholine receptors containing the human alpha6 subunit in recombinant mammalian cell lines has yet to be demonstrated. The resulting lack of selective ligands has hindered the evaluation of the role of alpha6-containing nicotinic receptors. We report that functional channels were recorded following co-transfection of human embryonic kidney (HEK-293) cells with a chimeric alpha6/alpha4 subunit and the beta4 nicotinic receptor subunit.

PSAB-OFP, a selective alpha 7 nicotinic receptor agonist, is also a potent agonist of the 5-HT3 receptor.

5-Hydroxytryptamine 3 (5-HT(3)) and alpha 7 nicotinic receptors share high sequence homology and pharmacological cross-reactivity. An assessment of the potential role of alpha 7 receptors in many neurophysiological processes, and hence their therapeutic value, requires the development of selective alpha 7 receptor agonists. We used a recently reported selective alpha 7 receptor agonist, (R)-(-)-5'Phenylspiro[1-azabicyclo[2.