Abstract
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 (α1β1γδ, α2β4, α3β2, α3β4, α4β2, α4β4, and α7) expressed in mammalian cells or Xenopus oocytes. At α2β4, α4β2, α4β4, and α7, but not α1β1γδ, α3β2, or α3β4, submaximal responses to nicotinic agonists were potentiated in a concentration-dependent manner by all compounds. At similar concentrations, no potentiation of 5-hydroxytryptamine, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, GABAA, and N-methyl-d-aspartate receptors or voltage-gated Na+ and Ca2+ channels was observed. Furthermore, these compounds did not inhibit acetylcholine esterase. Further profiling revealed that these compounds enhanced the potency and maximal efficacy of a range of nicotinic agonists at α4β2 nicotinic acetylcholine receptors, a profile typical of allosteric potentiators. At concentrations required for potentiation, the compounds did not displace [3H]epibatidine from the agonist-binding site, and potentiation was observed at all agonist concentrations, suggesting a noncompetitive mechanism of action. Blockade of common second messenger systems did not affect potentiation. At concentrations higher then required for potentiation the compounds also displayed intrinsic agonist activity, which was blocked by competitive and noncompetitive nicotinic acetylcholine receptor (nAChR) antagonists. These novel selective nicotinic receptor potentiators should help in clarifying the potential therapeutic utility of selective nAChR modulation for the treatment of central nervous system disorders.
Footnotes
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.104505.
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ABBREVIATIONS: nAChR, nicotinic acetylcholine receptor; 5-HT, 5-hydroxytryptamine; ACh, acetylcholine; NMDA, N-methyl-d-aspartate; FLIPR, fluorescent imaging plate reader; HEK, human embryonic kidney; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; SPA, scintillation proximity assay; PCR, polymerase chain reaction; 2087101, [2-(4-fluoro-phenylamino)-4-methyl-thiazol-5-yl]-thiophen-3-yl-methanone; 2087133, [2-(4-fluoro-phenylamin)-4-methyl-thiazol-5-yl]-p-tolyl-methanone; 1078733, benzo[1,3]dioxol-5-yl-[2-(4-fluoro-phenylamino)-4-methylthiazol-5-yl-methanone; TC-2559, [(E)-N-methyl-4-[3-(5-ethoxypyridin)yl]-3-buten-1-amine; dHβE, dihydro-β-erythroidine; PMA, phorbol myristate acetate; AM, acetomethyl ester; H-7, 1-(5-isoquinolinesulfonyl)-2-methyl piperazine dihydrochloride.
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↵1 Current affiliation: Amgen, Cambridge Research Center, Cambridge, MA.
- Received March 27, 2006.
- Accepted May 30, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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