NS 1738

Theoretical study of the binding profile of an allosteric modulator NS-1738 with a chimera structure of the alpha7 nicotinic acetylcholine receptor.[Pubmed:27711412]

Phys Chem Chem Phys. 2016 Oct 12;18(40):28003-28009.

Potentiation of the function of the alpha7 nicotinic acetylcholine receptor (alpha7-nAChR) is believed to provide a possible way for the treatment of cholinergic system dysfunctions such as Alzheimer's disease and schizophrenia. Positive allosteric modulators (PAMs) are able to augment the peak current response of the endogenous agonist of alpha7-nAChR by binding to some allosteric sites. In this study, the binding profile of a potent type I PAM, NS-1738, with a chimera structure (termed alpha7-AChBP) constructed from the extracellular domain of alpha7-nAChR and an acetylcholine binding protein was investigated with molecular docking, molecular dynamics simulation, and free energy calculation methods. We found that NS-1738 could bind to three allosteric sites of alpha7-AChBP, namely, the top pocket, the vestibule pocket and the agonist sub-pocket. NS-1738 has moderate binding affinities (-6.76 to -9.15 kcal mol(-1)) at each allosteric site. The urea group is critical for binding and can form hydrogen-bond interactions with the protein. The bulky trifluoromethyl group also has a great impact on the binding modes and binding affinities. We believe that our study provides valuable insight into the binding profiles of type I PAMs with alpha7-nAChR and is helpful for the development of novel PAMs.

The antinociceptive effects of nicotinic receptors alpha7-positive allosteric modulators in murine acute and tonic pain models.[Pubmed:23115222]

J Pharmacol Exp Ther. 2013 Jan;344(1):264-75.

The alpha7 nicotinic acetylcholine receptor (nAChR) subtype is abundantly expressed in the central nervous system and in the periphery. Recent evidence suggests that alpha7 nAChR subtypes, which can be activated by an endogenous cholinergic tone, comprising acetylcholine and the alpha7 nAChR agonist choline, play an important role in subchronic pain and inflammation. This study's objective was to test whether alpha7 nAChR positive allosteric modulators (PAMs) produce antinociception in in vivo mouse models of acute and persistent pain. Testing type I [N-(5-chloro-2-hydroxyphenyl)-N'-[2-chloro-5-(trifluoromethyl)phenyl] (NS1738)] and type II [1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl) (PNU-120596)] alpha7 nAChR PAMs in acute and persistent pain, we found that, although neither reduced acute thermal pain, only PNU-120596 dose-dependently attenuated paw-licking behavior in the formalin test. The long-acting effect of PNU-120596 in this test was in discordance with its pharmacokinetic profile in mice, which suggests the involvement of postreceptor signaling mechanisms. Our results with selective mitogen-activated protein kinase kinase inhibitor 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)butadiene monoethanolate (U0126) argues for an important role of extracellular signal-regulated kinase-1/2 pathways activation in PNU-120596's antinociceptive effects. The alpha7 antagonist MLA, administered intrathecally, reversed PNU-120596's effects, confirming PNU-120596's action, in part, through central alpha7 nAChRs. Importantly, tolerance to PNU-120596 was not developed after subchronic treatment of the drug. Surprisingly, PNU-120596's antinociceptive effects were blocked by NS1738. Our results indicate that type II alpha7 nAChR PAM PNU-120596, but not type I alpha7 nAChR PAM NS1738, shows significant antinociception effects in persistent pain models in mice.

An allosteric modulator of the alpha7 nicotinic acetylcholine receptor possessing cognition-enhancing properties in vivo.[Pubmed:17625074]

J Pharmacol Exp Ther. 2007 Oct;323(1):294-307.

Augmentation of nicotinic alpha7 receptor function is considered to be a potential therapeutic strategy aimed at ameliorating cognitive and mnemonic dysfunction in relation to debilitating pathological conditions, such as Alzheimer's disease and schizophrenia. In the present report, a novel positive allosteric modulator of the alpha7 nicotinic acetylcholine receptor (nAChR), 1-(5-chloro-2-hydroxy-phenyl)-3-(2-chloro-5-trifluoromethyl-phenyl)-urea (NS1738), is described. NS1738 was unable to displace or affect radioligand binding to the agonist binding site of nicotinic receptors, and it was devoid of effect when applied alone in electrophysiological paradigms. However, when applied in the presence of acetylcholine (ACh), NS1738 produced a marked increase in the current flowing through alpha7 nAChRs, as determined in both oocyte electrophysiology and patch-clamp recordings from mammalian cells. NS1738 acted by increasing the peak amplitude of ACh-evoked currents at all concentrations; thus, it increased the maximal efficacy of ACh. Oocyte experiments indicated an increase in ACh potency as well. NS1738 had only marginal effects on the desensitization kinetics of alpha7 nAChRs, as determined from patch-clamp studies of both transfected cells and cultured hippocampal neurons. NS1738 was modestly brain-penetrant, and it was demonstrated to counteract a (-)-scopolamine-induced deficit in acquisition of a water-maze learning task in rats. Moreover, NS1738 improved performance in the rat social recognition test to the same extent as (-)-nicotine, demonstrating that NS1738 is capable of producing cognitive enhancement in vivo. These data support the notion that alpha7 nAChR allosteric modulation may constitute a novel pharmacological principle for the treatment of cognitive dysfunction.

NS 1738 (NSC 213859) is a novel positive allosteric modulator of the α7 nAChR, with respect to positive modulation of α7 nAChR (EC50=3.4 μM in oocyte experiments).

NS 1738,501684-93-1,Natural Products,Nicotinic Receptor, buy NS 1738 , NS 1738 supplier , purchase NS 1738 , NS 1738 cost , NS 1738 manufacturer , order NS 1738 , high purity NS 1738