Abstract
Targeting α7 neuronal acetylcholine receptors (nAChRs) with selective agonists and positive allosteric modulators (PAMs) is considered a therapeutic approach for managing cognitive deficits in schizophrenia and Alzheimer's disease. In this study, we describe a novel type II α7 PAM, 4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744), that exhibits a unique pharmacological profile. In oocytes expressing α7 nAChRs, A-867744 potentiated acetylcholine (ACh)-evoked currents, with an EC50 value of ∼1 μM. At highest concentrations of A-867744 tested, ACh-evoked currents were essentially nondecaying. At lower concentrations, no evidence of a distinct secondary component was evident in contrast to 4-naphthalen-1-yl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonic acid amide (TQS), another type II α7 PAM. In the presence of A-867744, ACh concentration responses were potentiated by increases in potency, Hill slope, and maximal efficacy. When examined in rat hippocampus CA1 stratum radiatum interneurons or dentate gyrus granule cells, A-867744 (10 μM) increased choline-evoked α7 currents and recovery from inhibition/desensitization, and enhanced spontaneous inhibitory postsynaptic current activity. A-867744, like other α7 PAMs tested [1-(5-chloro-2-hydroxyphenyl)-3-(2-chloro-5-trifluoromethyl-phenyl)urea (NS1738), TQS, and 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea (PNU-120596)], did not displace the binding of [3H]methyllycaconitine to rat cortex α7* nAChRs. However, unlike these PAMs, A-867744 displaced the binding of the agonist [3H](1S,4S)-2,2-dimethyl-5-(6-phenylpyridazin-3-yl)-5-aza-2-azoniabicyclo[2.2.1]heptane (A-585539) in rat cortex, with a Ki value of 23 nM. A-867744 neither increased agonist-evoked responses nor displaced the binding of [3H]A-585539 in an α7/5-hydroxytryptamine3 (α7/5-HT3) chimera, suggesting an interaction distinct from the α7 N terminus or M2-3 loop. In addition, A-867744 failed to potentiate responses mediated by 5-HT3A or α3β4 and α4β2 nAChRs. In summary, this study identifies a novel and selective α7 PAM showing activity at recombinant and native α7 nAChRs exhibiting a unique pharmacological interaction with the receptor.
Footnotes
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This work was supported by Abbott. All authors are employees of Abbott.
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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.109.151886.
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ABBREVIATIONS: nAChR, neuronal acetylcholine receptor; 5-HT, 5-hydroxytryptamine; PAM, positive allosteric modulator; SB-206553, 3,5-dihydro-5-methyl-N-3-pyridinylbenzo[1,2-b:4,5-b′]di pyrrole-1(2H)-carboxamide; PNU-120596, 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea; TQS, 4-naphthalen-1-yl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonic acid amide; CCMI (XY4083), N-(4-chlorophenyl)-[[(4-chlorophenyl)amino]methylene]-3-methyl-5-isoxazoleacet-amide; 5-HI, 5-hydroxyindole; A-867744, 4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)-benzenesulfonamide; MLA, methyllycaconitine; PNU-282987, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride; A-585539, (1S,4S)-2,2-dimethyl-5-(6-phenylpyridazin-3-yl)-5-aza-2-azoniabicyclo[2.2.1]heptane; NS6784, 4-(5-phenyl-[1,3,4]oxadiazol-2-yl)-1,4-diaza-bicyclo-[3.2.2]nonane; NS1738, 1-(5-chloro-2-hydroxyphenyl)-3-(2-chloro-5-trifluoromethyl-phenyl)urea; TTX, tetrodotoxin; APV, 2-amino-5-phosphonovalerate; CNQX, 6-cyano-2,3-dihydroxy-7-nitroquinoxaline; FMP, fast membrane potential; HEK, human embryonic kidney; FLIPR, fluorometric imaging plate reader; LY-2087101, [2-(4-fluoro-phenylamino)-4-methyl-thiazol-5-yl]-thiopen-3-yl-methanone; ACSF, artificial cerebrospinal fluid; IPSC, inhibitory postsynaptic current; P, puff application; Hpot, holding potential.
- Received February 11, 2009.
- Accepted April 21, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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