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

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 K_i 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-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.