title: Identification and pharmacological profile of a new class of selective nicotinic acetylcholine receptor potentiators.
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 (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. At similar concentrations, no potentiation of 5-hydroxytryptamine, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, GABA(A), and N-methyl-d-aspartate receptors or voltage-gated Na(+) and Ca(2+) 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 alpha4beta2 nicotinic acetylcholine receptors, a profile typical of allosteric potentiators. At concentrations required for potentiation, the compounds did not displace [(3)H]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.
authors.affiliation: Eli Lilly and Company Ltd., Lilly Research Centre, Windlesham, Surrey GU20 6PH, UK.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Broad
authors.forename: Ruud
authors.initials: R
authors.lastname: Zwart
authors.forename: Kathy H
authors.initials: KH
authors.lastname: Pearson
authors.forename: Martin
authors.initials: M
authors.lastname: Lee
authors.forename: Louise
authors.initials: L
authors.lastname: Wallace
authors.forename: Gordon I
authors.initials: GI
authors.lastname: McPhie
authors.forename: Renee
authors.initials: R
authors.lastname: Emkey
authors.forename: Sean P
authors.initials: SP
authors.lastname: Hollinshead
authors.forename: Colin P
authors.initials: CP
authors.lastname: Dell
authors.forename: S Richard
authors.initials: SR
authors.lastname: Baker
authors.forename: Emanuele
authors.initials: E
authors.lastname: Sher
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002460:Cell Line; D004357:Drug Synergism; D005702:Galantamine / Q000494:pharmacology; D006801:Humans; D018722:Nicotinic Agonists / Q000494:pharmacology*; D021122:Protein Subunits; D011725:Pyridines / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000187:drug effects*; D011994:Recombinant Proteins / Q000187:drug effects; D014982:Xenopus laevis
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D018722:Nicotinic Agonists; D021122:Protein Subunits; D011725:Pyridines; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins; D005702:Galantamine; C082748:epibatidine