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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on May 31, 2006; DOI: 10.1124/jpet.106.104505

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Received for publication March 27, 2006.
Revised May 25, 2006.
Accepted for publication May 30, 2006.

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

Lisa M Broad 1, Ruud Zwart 2, Kathy Pearson 1, Martin Lee 1, Louise Wallace 1, Gordon Mc Phie 1, Renee Emkey 3, Sean Hollinshead 1, Colin Dell 1, Richard Baker 1, Emanuele Sher 2*

1 Eli Lilly and Co 2 Eli Lilly and Co. 3 Amgen

* Address correspondence to: E-mail: sher_emanuele{at}lilly.com

Abstract

We here report the discovery, by high-throughput screening, of 3 novel (2-amino-5-keto)thiazole compounds, which act as selective potentiators of nicotinic acetylcholine receptors. Compound selectivity was assessed at 7 human nicotinic acetylcholine receptors ({alpha}1{beta}1{gamma}{delta}, {alpha}2{beta}4, {alpha}3{beta}2, {alpha}3{beta}4, {alpha}4{beta}2, {alpha}4{beta}4, {alpha}7) expressed in mammalian cells or Xenopus oocytes. At {alpha}2{beta}4, {alpha}4{beta}2, {alpha}4{beta}4 and {alpha}7, but not {alpha}1{beta}{gamma}{delta}, {alpha}3{beta}2 or {alpha}3{beta}4, sub-maximal responses to nicotinic agonists were potentiated in a concentration dependent manner by all compounds. At similar concentrations no potentiation of 5-HT3, AMPA, GABAA and NMDA 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 {alpha}4{beta}2 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 non-competitive 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 non-competitive nAChR antagonists. These novel selective nicotinic receptor potentiators should help in clarifying the potential therapeutic utility of selective nAChR modulation for the treatment of CNS disorders.


Key words: allosteric, central nervous system, ligand-gated, nicotinic, potentiator, receptor


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