RESEARCH PAPER The α7 nicotinic receptor dual allosteric agonist and positive allosteric modulator GAT107 reverses nociception inmousemodels of inflammatory and neuropathic pain
نویسندگان
چکیده
Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA, Experimental Animals Breeding and Research Center, Faculty of Medicine, Uludag University, Bursa, Turkey, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA, Department of Pharmacology and Toxicology, King Saud University, Riyadh, Saudi Arabia, Department of Pharmacology, Faculty of Medicine, Uludag University, Bursa, Turkey, and Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA
منابع مشابه
The activity of GAT107, an allosteric activator and positive modulator of α7 nicotinic acetylcholine receptors (nAChR), is regulated by aromatic amino acids that span the subunit interface.
GAT107, the (+)-enantiomer of racemic 4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide, is a strong positive allosteric modulator (PAM) of α7 nicotinic acetylcholine receptor (nAChR) activation by orthosteric agonists with intrinsic allosteric agonist activities. The direct activation produced by GAT107 in electrophysiological studies is observed only as long as GA...
متن کاملExpeditious synthesis, enantiomeric resolution, and enantiomer functional characterization of (4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide (4BP-TQS): an allosteric agonist-positive allosteric modulator of α7 nicotinic acetylcholine receptors.
An expeditious microwave-assisted synthesis of 4BP-TQS, its enantiomeric separation, and their functional evaluation is reported. Electrophysiological characterization in Xenopus oocytes revealed that activity exclusively resided in the (+)-enantiomer 1b (GAT107) and (-)-enantiomer 1a did not affect its activity when coapplied. X-ray crystallography studies revealed the absolute stereochemistry...
متن کاملCritical Molecular Determinants of α7 Nicotinic Acetylcholine Receptor Allosteric Activation: SEPARATION OF DIRECT ALLOSTERIC ACTIVATION AND POSITIVE ALLOSTERIC MODULATION.
The α7 nicotinic acetylcholine receptors (nAChRs) are uniquely sensitive to selective positive allosteric modulators (PAMs), which increase the efficiency of channel activation to a level greater than that of other nAChRs. Although PAMs must work in concert with "orthosteric" agonists, compounds such as GAT107 ((3aR,4S,9bS)-4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulf...
متن کاملSpinal noradrenergic activation mediates allodynia reduction from an allosteric adenosine modulator in a rat model of neuropathic pain.
Activation of adenosine A1 receptors by endogenous adenosine or synthetic agonists produces anti-nociception in animal models of acute pain and also reduces hypersensitivity in models of inflammatory and nerve-injury pain. Allosteric adenosine modulators facilitate adenosine agonist binding to the A1 receptor. The purpose of the current study was to examine the effect, mechanisms of action, and...
متن کاملContrasting Properties of α7-Selective Orthosteric and Allosteric Agonists Examined on Native Nicotinic Acetylcholine Receptors
Subtype-selective ligands are important tools for the pharmacological characterisation of neurotransmitter receptors. This is particularly the case for nicotinic acetylcholine receptors (nAChRs), given the heterogeneity of their subunit composition. In addition to agonists and antagonists that interact with the extracellular orthosteric nAChR binding site, a series of nAChR allosteric modulator...
متن کامل