Discovery of 4-(5-(4-Chlorophenyl)-2-methyl-3-propionyl-1<i>H</i>-pyrrol-1-yl)benzenesulfonamide (A-867744) as a Novel Positive Allosteric Modulator of the α7 Nicotinic Acetylcholine Receptor

Faghih, Ramin; Gopalakrishnan, Sujatha M.; Grønlien, Jens Halvard; Malysz, John; Briggs, Clark A.; Wetterstrand, Caroline; Ween, Hilde; Curtis, Michael; Sarris, Kathy; Gfesser, Gregory A.; El-Kouhen, Rachid; Robb, Holly M.; Radek, Richard J.; Marsh, Kennan C.; Bunnelle, William H.; Gopalakrishnan, Murali

doi:10.1021/jm9003818

Cited by 49 publications

(40 citation statements)

References 44 publications

(83 reference statements)

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“…Type-II nAChR PAMs potentiate ACh-induced peak current and prolong the time course of the agonist-evoked response by suppressing the extent of fast desensitization and by increasing the contribution of a slow desensitizing current. Two representative type-II PAMs include PNU-120596 (eg, EC 50 ¼ 1.5 mM; fourfold shift) and A-867744 (Hurst et al, 2005;Gronlien et al, 2007;Malysz et al, 2009;Faghih et al, 2009). Interestingly, both type-I and II a 7 nAChR PAMs produced efficacy in preclinical models, including reversal of auditory gating deficits in DBA/2 mice or after amphetamine challenge; reversal of MK-801-induced deficits in PPI and other pharmacological disruptions in novelty-induced exploratory activity; Morris water maze; and social interaction (Hurst et al, 2005;Timmermann et al, 2007;Faghih et al, 2009).…”

Section: Preclinical Studies Of a 7 Nachr Positive Allosteric Modulatorsmentioning

confidence: 99%

“…Two representative type-II PAMs include PNU-120596 (eg, EC 50 ¼ 1.5 mM; fourfold shift) and A-867744 (Hurst et al, 2005;Gronlien et al, 2007;Malysz et al, 2009;Faghih et al, 2009). Interestingly, both type-I and II a 7 nAChR PAMs produced efficacy in preclinical models, including reversal of auditory gating deficits in DBA/2 mice or after amphetamine challenge; reversal of MK-801-induced deficits in PPI and other pharmacological disruptions in novelty-induced exploratory activity; Morris water maze; and social interaction (Hurst et al, 2005;Timmermann et al, 2007;Faghih et al, 2009). Interestingly, these preliminary findings have been observed with administration of the nAChR PAMs alone, indicating that there is sufficient cholinergic tone on a 7 nAChRs for a viable allosteric modulator approach in vivo.…”

Section: Preclinical Studies Of a 7 Nachr Positive Allosteric Modulatorsmentioning

confidence: 99%

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Muscarinic and Nicotinic Acetylcholine Receptor Agonists and Allosteric Modulators for the Treatment of Schizophrenia

Jones

Byun

Bubser

2011

Neuropsychopharmacol

186

139

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Muscarinic and nicotinic acetylcholine (ACh) receptors (mAChRs and nAChRs) are emerging as important targets for the development of novel treatments for the symptoms associated with schizophrenia. Preclinical and early proof-of-concept clinical studies have provided strong evidence that activators of specific mAChR (M 1 and M 4 ) and nAChR (a 7 and a 2 b 4 ) subtypes are effective in animal models of antipsychotic-like activity and/or cognitive enhancement, and in the treatment of positive and cognitive symptoms in patients with schizophrenia. While early attempts to develop selective mAChR and nAChR agonists provided important preliminary findings, these compounds have ultimately failed in clinical development due to a lack of true subtype selectivity and subsequent dose-limiting adverse effects. In recent years, there have been major advances in the discovery of highly selective activators for the different mAChR and nAChR subtypes with suitable properties for optimization as potential candidates for clinical trials. One novel strategy has been to identify ligands that activate a specific receptor subtype through actions at sites that are distinct from the highly conserved ACh-binding site, termed allosteric sites. These allosteric activators, both allosteric agonists and positive allosteric modulators, of mAChR and nAChR subtypes demonstrate unique mechanisms of action and high selectivity in vivo, and may provide innovative treatment strategies for schizophrenia.

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Section: Preclinical Studies Of a 7 Nachr Positive Allosteric Modulatorsmentioning

confidence: 99%

Section: Preclinical Studies Of a 7 Nachr Positive Allosteric Modulatorsmentioning

confidence: 99%

Muscarinic and Nicotinic Acetylcholine Receptor Agonists and Allosteric Modulators for the Treatment of Schizophrenia

Jones

Byun

Bubser

2011

Neuropsychopharmacol

186

139

View full text Add to dashboard Cite

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“…Among type II PAMs, we can name PNU-120596 [N-(5-chloro-2,4-dimethoxyphenyl)-N 0 -(5-methyl-3-isoxazolyl)-urea] (Hurst et al, 2005;Young et al, 2008;Barron et al, 2009;Dunlop et al, 2009;López-Hernández et al, 2009), the pyrrole-sulfonamide derivative A-867744 [4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide] (Faghih et al, 2009), the tetrahydroquinoline derivative TQS (4-naphthalene-1-yl-3a,4,5,9b-tetrahydro-3-H-cyclopenta[c]quinoline-8-sulfonic acid amide) , the anthelmintic agent ivermectin (Krause et al, 1998), the indolic alkaloid desformylflustrabromine Kim et al, 2007;Weltzin and Schulte, 2010), and the morphine derivative codeine (Storch et al, 1995). Type II modulators exert a much greater effect on AChR activation than agonists alone and decrease desensitization.…”

Section: A Positive Allosteric Modulatorsmentioning

confidence: 99%

“…In animal models, PNU-120596 (Hurst et al, 2005), A-867744 (Faghih et al, 2009), compound 6 (Ng et al, 2007, SB-206553 (Dunlop et al, 2009), and NS-1738(Timmermann et al, 2007, can partially restore auditory gating deficits in mutant mice or those induced by drugs. In this regard, these PAMs might be used to treat the symptoms of schizophrenia.…”

Section: Positive Allosteric Modulatorsmentioning

confidence: 99%

Positive and negative modulation of nicotinic receptors

Arias

2010

Advances in Protein Chemistry and Structural Biology

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“…A-867744 (36), in oocytes expressing α7 nAChR, potentiated ACh-evoked currents with an EC 50 of 1 μM [184]. In the presence of A-867744, ACh concentration responses were potentiated by increases in potency, Hill slope, and maximal efficacy.…”

Section: α7 Nachr-positive Allosteric Modulators For Schizophreniamentioning

confidence: 99%

Nicotinic Acetylcholine Receptor Modulators

Mazurov¹,

Yohannes

2014

Small Molecule Therapeutics for Schizophrenia

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Nicotine and its pharmacology have long been associated with schizophrenia and its epidemiology and treatment. Schizophrenics use nicotine in its major delivery form of cigarettes at a significantly higher incidence than the general population (80-90% vs. 25-30% of the general population) and even than those diagnosed with other psychiatric diseases. Various studies have demonstrated that cigarette smoking transiently restores cognitive and sensory deficits in patients with schizophrenia/schizoaffective disorders. Conversely, smoking cessation appears to exacerbate the symptoms of the disease. A disturbance of nicotinic receptor expression, affecting the α7 and α4β2 subunits, in various cerebral areas has been revealed in postmortem binding studies. Genetic linkage studies have also demonstrated that the α7 subunit is involved in the pathology of schizophrenia. Much of the drug discovery and development efforts in the nAChR field have focused on α7 and α4β2 nAChR subtypes. These include studies using nicotine and varenicline (the smoking cessation drug marketed as Chantix or Champix) as well as numerous other small-molecule therapeutics targeting these receptor subtypes. While some early studies included α4β2 modulators, the large majority of drug development of nAChR ligands for schizophrenia have been α7 agonists and partial agonists. Such therapeutics are in late-stage development and may constitute a breakthrough for the treatment of schizophrenia with safe and effective medicines.

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Discovery of 4-(5-(4-Chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744) as a Novel Positive Allosteric Modulator of the α7 Nicotinic Acetylcholine Receptor

Cited by 49 publications

References 44 publications

Muscarinic and Nicotinic Acetylcholine Receptor Agonists and Allosteric Modulators for the Treatment of Schizophrenia

Muscarinic and Nicotinic Acetylcholine Receptor Agonists and Allosteric Modulators for the Treatment of Schizophrenia

Positive and negative modulation of nicotinic receptors

Nicotinic Acetylcholine Receptor Modulators

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