NS383 Selectively Inhibits Acid-Sensing Ion Channels Containing 1a and 3 Subunits to Reverse Inflammatory and Neuropathic Hyperalgesia in Rats.

AIMS: Here, we investigate the pharmacology of NS383, a novel small molecule inhibitor of acid-sensing ion channels (ASICs). METHODS: ASIC inhibition by NS383 was characterized in patch-clamp electrophysiological studies. Analgesic properties were evaluated in four rat behavioral models of pain. RESULTS: NS383 inhibited H(+)-activated currents recorded from rat homomeric ASIC1a, ASIC3, and heteromeric ASIC1a+3 with IC50 values ranging from 0.61 to 2.2 µM. However, NS383 was completely inactive at homomeric ASIC2a. Heteromeric receptors containing AISC2a, such as ASIC1a+2a and ASIC2a+3, were only partially inhibited, presumably as a result of stoichiometry-dependent binding. NS383 (10-60 mg/kg, i.p.), amiloride (50-200 mg/kg, i.p.), acetaminophen (100-400 mg/kg, i.p.), and morphine (3-10 mg/kg, i.p.) all dose-dependently attenuated nocifensive behaviors in the rat formalin test, reversed pathological inflammatory hyperalgesia in complete Freund's adjuvant-inflamed rats, and reversed mechanical hypersensitivity in the chronic constriction injury model of neuropathic pain. However, in contrast to acetaminophen and morphine, motor function was unaffected by NS383 at doses at least 8-fold greater than those that were effective in pain models, whilst analgesic doses of amiloride were deemed to be toxic. CONCLUSIONS: NS383 is a potent and uniquely selective inhibitor of rat ASICs containing 1a and/or 3 subunits. It is well tolerated and capable of reversing pathological painlike behaviors, presumably via peripheral actions, but possibly also via actions within central pain circuits.

An allosteric modulator of the alpha7 nicotinic acetylcholine receptor possessing cognition-enhancing properties in vivo.

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.