nAChRα4&β2 x α4β2 receptor

Last update 08 May 2025

Basic Info

Related Targets

nAChRα4&β2α4β2 receptor

Drugs associated with nAChRα4&β2 x α4β2 receptor

TC-2696

Target

nAChRα4&β2 x α4β2 receptor

Mechanism

nAChRα4&β2 agonists [+1]

Active Org.-

Originator Org.

Catalyst KK

Active Indication-

Inactive Indication

Dyskinesia, Drug-Induced [+1]

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with nAChRα4&β2 x α4β2 receptor

100 Translational Medicine associated with nAChRα4&β2 x α4β2 receptor

0 Patents (Medical) associated with nAChRα4&β2 x α4β2 receptor

Literatures (Medical) associated with nAChRα4&β2 x α4β2 receptor

28 Dec 2017·Journal of Medicinal ChemistryQ1 · MEDICINE

Highly Selective and Potent α4β2 nAChR Antagonist Inhibits Nicotine Self-Administration and Reinstatement in Rats

Q1 · MEDICINE

Article

Author: Toll, Lawrence ; Schoch, Jennifer ; Welmaker, Gregory S. ; Chen, Wenteng ; Zhang, Yaohong ; Debevec, Ginamarie ; Cippitelli, Andrea ; Houghten, Richard A. ; Yu, Yongping ; Ozawa, Akihiko ; Giulianotti, Marc A. ; Liu, Huan ; Wu, Jinhua

The α4β2 nAChR is the most predominant subtype in the brain and is a well-known culprit for nicotine addiction. Previously we presented a series of α4β2 nAChR selective compounds that were discovered from a mixture-based positional-scanning combinatorial library. Here we report further optimization identified highly potent and selective α4β2 nAChR antagonists 5 (AP-202) and 13 (AP-211). Both compounds are devoid of in vitro agonist activity and are potent inhibitors of epibatidine-induced changes in membrane potential in cells containing α4β2 nAChR, with IC₅₀ values of approximately 10 nM, but are weak agonists in cells containing α3β4 nAChR. In vivo studies show that 5 can significantly reduce operant nicotine self-administration and nicotine relapse-like behavior in rats at doses of 0.3 and 1 mg/kg. The pharmacokinetic data also indicate that 5, via sc administration, is rapidly absorbed into the blood, reaching maximal concentration within 10 min with a half-life of less than 1 h.

01 Sep 2012·British Journal of Pharmacology

Augmentation of cognitive function by NS9283, a stoichiometry‐dependent positive allosteric modulator of α2‐ and α4‐containing nicotinic acetylcholine receptors

Article

Author: Smith M ; Dyhring T ; Sandager-Nielsen K ; Peters D ; Christensen Jk ; Jacobsen Am ; Olsen Gm ; Grunnet M ; Nielsen Eø ; Kohlhaas K ; Ahring Pk ; Timmermann Db

BACKGROUND AND PURPOSEPositive allosteric modulation of α4β2 nicotinic acetylcholine (nACh) receptors could add a new dimension to the pharmacology and therapeutic approach to these receptors. The novel modulator NS9283 was therefore tested extensively.EXPERIMENTAL APPROACHEffects of NS9283 were evaluated in vitro using fluorescence‐based Ca2+ imaging and electrophysiological voltage clamp experiments in Xenopus oocytes, mammalian cells and thalamocortical neurons. In vivo the compound was tested in models covering a range of cognitive domains in mice and rats.KEY RESULTSNS9283 was shown to increase agonist‐evoked response amplitude of (α4)3(β2)2 nACh receptors in electrophysiology paradigms. (α2)3(β2)2, (α2)3(β4)2 and (α4)3(β4)2 were modulated to comparable extents, but no effects were detected at α3‐containing or any 2α : 3β stoichiometry nACh receptors. Native nACh receptors in thalamocortical neurons similarly displayed DHβE‐sensitive currents that were receptive to modulation. NS9283 had favourable effects on sensory information processing, as shown by reversal of PCP‐disrupted pre‐pulse inhibition. NS9283 further improved performance in a rat model of episodic memory (social recognition), a rat model of sustained attention (five‐choice serial reaction time task) and a rat model of reference memory (Morris water maze). Importantly, the effects in the Morris water maze could be fully reversed with mecamylamine, a blocker of nACh receptors.CONCLUSIONS AND IMPLICATIONSThese results provide compelling evidence that positive allosteric modulators acting at the (α4)3(β2)2 nACh receptors can augment activity across a broad range of cognitive domains, and that α4β2 nACh receptor allosteric modulation therefore constitutes a promising therapeutic approach to symptomatic treatment of cognitive impairment.

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