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 ␣7 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 ␣7 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 ␣7 nAChRs, A-867744 potentiated acetylcholine (ACh)-evoked currents, with an EC 50 value of ϳ1 M. 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 ␣7 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 M) increased choline-evoked ␣7 currents and recovery from inhibition/desensitization, and enhanced spontaneous inhibitory postsynaptic current activity. A-867744, like other ␣7 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 ␣7* nAChRs. However, unlike these PAMs, A-867744 displaced the binding of the agonist 3 H]A-585539 in an ␣7/5-hydroxytryptamine 3 (␣7/5-HT 3 ) chimera, suggesting an interaction distinct from the ␣7 N terminus or M2-3 loop. In addition, A-867744 failed to potentiate responses mediated by 5-HT 3〈 or ␣3␤4 and ␣4␤2 nAChRs. In summary, this study identifies a novel and selective ␣7 PAM showing activity at recombinant and native ␣7 nAChRs exhibiting a unique pharmacological interaction with the receptor.Neuronal nicotinic acetylcholine receptors (nAChRs) belong to the pentameric superfamily of ligand-gated ion channels that includes 5-HT 3 , GABA A/C , and glycine receptors. These receptors are composed of either homomeric ␣ or hetThis work was supported by Abbott. All authors are employees of Abbott. Article, publication date, and citation information can be found at

In Vitro Pharmacological Characterization of a Novel Selective α7 Neuronal Nicotinic Acetylcholine Receptor Agonist ABT-107

“…In additional experiments, the ␣7 nAChR response in IMR-32 cells and cortical cultures was assessed by using a combination of a selective ␣7 nAChR PAM, A-867744, or PNU-120596 and the ␣7 agonist ABT-107 according to methods published previously (Malysz et al, 2009a;Ween et al, 2010). The responses were normalized to wells receiving coapplication of ABT-107 (0.1 M) and either 10 M A-867744 or PNU-120596.…”

“…Whole cell patch-clamp recordings from brain slices were carried out as described recently (Malysz et al, 2009a). Briefly, hippocampus brain slices were prepared from 15-to 22-day-old male Sprague-Dawley rats (Charles River Laboratories, Inc.).…”

“…ABT-107 exhibits weak interaction with non-␣7 nAChRs, 5-HT 3 , and H 3 receptors. The effects of this compound are described herein at native ␣7 nAChRs, in an in vitro glutamate neurotoxicity model, and evaluated in the context of interaction with the selective ␣7 positive allosteric modulators (PAMs) N- [(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride (PNU-120596) and 4-[5-(4-chloro-phenyl)-2-methyl-3-propionyl-pyrrol-1-yl]-benzenesulfonamide (A-867744) Malysz et al, 2009a). This study and the accompanying report by Bitner et al (2010) show that selective targeting of ␣7 nAChRs has unique potential for modulating pathways of therapeutic relevance for both symptomatic alleviation and disease modification associated with central nervous system (CNS) disorders such as AD.…”

Characterization of 2-[[4-Fluoro-3-(trifluoromethyl)phenyl]amino]-4-(4-pyridinyl)-5-thiazolemethanol (JNJ-1930942), a Novel Positive Allosteric Modulator of the α7 Nicotinic Acetylcholine Receptor

“…More recently, several novel compounds have been designed as potent ␣ 7 nAChR-positive allosteric modulators (PAMs) (Faghih et al, 2008;Malysz et al, 2009). PAMs bind to a site distinct from the orthosteric agonist binding pocket, and in so doing, they potentiate the agonistevoked response.…”

“…Type I PAMs predominantly affect the apparent agonistinduced peak current, leaving the agonist-induced desensitization and deactivation processes largely intact, whereas type II PAMs affect the peak current, evoke a secondary weakly decaying current, and reactivate desensitized currents. Examples of type I PAMs are N-(4-chlorophenyl)- [[(4-chlorophenyl)amino] methylene]-3-methyl-5-isoxazoleacetamide (XY-4083), [2-(4-fluoro-phenylamino)-4-methyl-thiazol-5-yl]-thiopen-3-yl-methanone (LY2087101), and N-(5-chloro-2-hydroxyphenyl)-NЈ- [2-chloro-5-(trifluoromethyl)phenyl]urea (NS-1738); typical type II PAMs are 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methylisoxazol-3-yl)-urea (PNU-120596), 4-naphthalen-1-yl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonic acid amide (TQS), and 4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744) (Bertrand and Gopalakrishnan, 2007;Grønlien et al, 2007;Malysz et al, 2009). Whether type I and II PAMs bind to similar or different binding sites is a topic of current research.…”