In Vitro Pharmacological Characterization of a Novel Allosteric Modulator of α7 Neuronal Acetylcholine Receptor, 4-(5-(4-Chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744), Exhibiting Unique Pharmacological Profile

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 330; no. 1; p. 257
• Main Authors: John Malysz, Jens Halvard Grønlien, David J. Anderson, Monika HÃ¥kerud, Kirsten Thorin-Hagene, Hilde Ween, Caroline Wetterstrand, Clark A. Briggs, Ramin Faghih, William H. Bunnelle, Murali Gopalakrishnan
• Format: Journal Article
• Language: English
• Published: American Society for Pharmacology and Experimental Therapeutics 01.07.2009
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.109.151886

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-1 H -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 EC 50 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-3 a ,4,5,9 b -tetrahydro-3 H -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 [ 3 H]methyllycaconitine to rat cortex α7 * nAChRs. However, unlike these PAMs, A-867744 displaced the binding of the agonist [ 3 H](1 S ,4 S )-2,2-dimethyl-5-(6-phenylpyridazin-3-yl)-5-aza-2-azoniabicyclo[2.2.1]heptane (A-585539) in rat cortex, with a K i value of 23 nM. A-867744 neither increased agonist-evoked responses nor displaced the binding of [ 3 H]A-585539 in an α7/5-hydroxytryptamine 3 (α7/5-HT 3 ) 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-HT 3A 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.