title: In vitro pharmacological characterization of a novel allosteric modulator of alpha 7 neuronal acetylcholine receptor, 4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744), exhibiting unique pharmacological profile.
abstract: Targeting alpha7 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 alpha7 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 alpha7 nAChRs, A-867744 potentiated acetylcholine (ACh)-evoked currents, with an EC(50) value of approximately 1 microM. 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 alpha7 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 microM) increased choline-evoked alpha7 currents and recovery from inhibition/desensitization, and enhanced spontaneous inhibitory postsynaptic current activity. A-867744, like other alpha7 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 alpha7(*) nAChRs. However, unlike these PAMs, A-867744 displaced the binding of the agonist [(3)H](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 K(i) value of 23 nM. A-867744 neither increased agonist-evoked responses nor displaced the binding of [(3)H]A-585539 in an alpha7/5-hydroxytryptamine(3) (alpha7/5-HT(3)) chimera, suggesting an interaction distinct from the alpha7 N terminus or M2-3 loop. In addition, A-867744 failed to potentiate responses mediated by 5-HT(3A) or alpha3beta4 and alpha4beta2 nAChRs. In summary, this study identifies a novel and selective alpha7 PAM showing activity at recombinant and native alpha7 nAChRs exhibiting a unique pharmacological interaction with the receptor.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Rd., Abbott Park, IL 60064-6125, USA. john.malysz@abbott.com
authors.forename: John
authors.initials: J
authors.lastname: Malysz
authors.forename: Jens Halvard
authors.initials: JH
authors.lastname: Grønlien
authors.forename: David J
authors.initials: DJ
authors.lastname: Anderson
authors.forename: Monika
authors.initials: M
authors.lastname: Håkerud
authors.forename: Kirsten
authors.initials: K
authors.lastname: Thorin-Hagene
authors.forename: Hilde
authors.initials: H
authors.lastname: Ween
authors.forename: Caroline
authors.initials: C
authors.lastname: Wetterstrand
authors.forename: Clark A
authors.initials: CA
authors.lastname: Briggs
authors.forename: Ramin
authors.initials: R
authors.lastname: Faghih
authors.forename: William H
authors.initials: WH
authors.lastname: Bunnelle
authors.forename: Murali
authors.initials: M
authors.lastname: Gopalakrishnan
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002460:Cell Line; D018678:Cholinergic Agents / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000096926:Benzenesulfonamides
chemical_list: D018678:Cholinergic Agents; D011758:Pyrroles; D011978:Receptors, Nicotinic; D013449:Sulfonamides; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000096926:Benzenesulfonamides; C542089:4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide; C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat