nAChR α4/β2/α5 agonists(Nicotinic acetylcholine receptor alpha4/beta2/alpha5 agonists), α3β4 receptor agonists(Neuronal acetylcholine receptor; alpha3/beta4 agonists)

Therapeutic Areas

Other Diseases

Active Indication-

Inactive Indication

Behavioural disorders

Originator Organization

Pfizer Inc.

Active Organization-

Inactive Organization

Pfizer Inc.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

100 Clinical Results associated with CP-601932

100 Translational Medicine associated with CP-601932

100 Patents (Medical) associated with CP-601932

Literatures (Medical) associated with CP-601932

01 Sep 2018·PsychopharmacologyQ3 · MEDICINE

The contribution of agonist and antagonist activities of α4β2* nAChR ligands to smoking cessation efficacy: a quantitative analysis of literature data

Q3 · MEDICINE

Review

Author: Hurst, Raymond S ; Rollema, Hans

RATIONALE AND OBJECTIVETwo mechanisms underlie smoking cessation efficacies of α4β2* nicotinic acetylcholine receptor (nAChR) agonists: a "nicotine-like" agonist activity reduces craving by substituting for nicotine during a quit attempt, and a "nicotine-blocking" antagonist activity attenuates reinforcement by competing with inhaled nicotine during a relapse. To evaluate the contribution of each mechanism to clinical efficacy, we estimated the degree of agonist and antagonist activities of nicotine replacement therapy (NRT), varenicline, cytisine, and the discontinued nAChR agonists dianicline, ABT-418, ABT-089, CP-601927, and CP-601932, relative to the functional effects of nicotine from smoking.METHODSFunctional activities that occur in vivo with clinical doses were predicted from literature data on binding and functional potencies at the target α4β2 nAChR, as well as at α6β2* nAChRs, and from estimates of free drug exposures in human brain. Agonist activity is comprised of nAChR activation and desensitization, which were expressed as percentages of desensitization and activation by nicotine from smoking. Antagonist activity was expressed as the reduction in nAChR occupancy by nicotine during smoking in the presence of an agonist.RESULTSComparisons with odds ratios at end of treatment suggest that extensive α4β2 and α6β2* nAChR desensitization combined with α6β2* nAChR activation at similar levels as nicotine from smoking is associated with clinical efficacy (NRT, varenicline, cytisine, ABT-418). Effective competition with inhaled nicotine for α4β2 and α6β2* nAChRs further improves clinical efficacy (varenicline). Other discontinued nAChR agonists have lower agonist and antagonist activities at α4β2 nAChRs and are inactive or less efficacious than NRT (dianicline, ABT-089, CP-601927, CP-601932).CONCLUSIONThree pharmacological effects appear to be key factors underlying smoking cessation efficacy: the degree of activation of α6β2* nAChRs, desensitization of α4β2 and α6β2* nAChRs (agonist activity), and the reduction of nicotine occupancy at α4β2 and α6β2* nAChRs (antagonist activity). No single activity is dominant, and the level of smoking cessation efficacy depends on the profile of these activities achieved at clinical doses. While adequate agonist activity alone seems sufficient for a clinical effect (e.g., NRT, cytisine), clinical efficacy is improved with substantial competitive antagonism of α4β2 nAChRs, i.e., if the drug has a dual agonist-antagonist mechanism of action (e.g., varenicline).

01 May 2012·Recent Patents on CNS Drug Discovery

Cholinergic Receptor System as a Target for Treating Alcohol Abuse and Dependence

Review

Author: Prendergast, Mark A. ; Rahman, Shafiqur

Alcohol dependence and other alcohol use disorders are major public health problems. Due to the limitations in efficacy with current medications for the management of alcohol abuse and dependence, there is a need for alterantive pharmacotherapies. Emerging preclinical and clinical data indicate that brain nicotinic acetylcholine receptors (nAChRs), a heterogeneous family of ion channels expressed in the mammalian brain, are critical targets for the development of pharmacotherapies for alcohol abuse and dependence. Evidence suggests that the effects of nAChR partial agonists and antagonists have promise for the management of alcohol dependence and other alcohol use disorders. The present review summarizes information on the most recent pharmacotherapies targeting nAChRs, including cytisine, sazetidine A, varenicline, lobeline mecamylamine, PF-4575180 and CP-601932, that are able to treat alcohol dependence. The role of α4β2*, α3β4* and/or other subtypes associated effects in reducing voluntary alcohol consumption or modulate alcohol drinking behavior in animal models and humans are reviewed. Patents discussed include those targeting α4β2* and α7 subtypes as well as cholinesterase inhibitors. Future research indicating the ability of nAChR based compounds to reduce alcohol consumption or modulate alcohol drinking behavior in preclinical and clinical studies, are also discussed.

01 Feb 2011·NeuropsychopharmacologyQ1 · MEDICINE

Partial Agonists of the α3β4* Neuronal Nicotinic Acetylcholine Receptor Reduce Ethanol Consumption and Seeking in Rats

Q1 · MEDICINE

Article

Author: Jotham W Coe ; John Lowe ; Raymond S Hurst ; Pia Steensland ; Jeffrey A Simms ; Joan Holgate ; Selena E Bartlett ; Hans Rollema ; Susmita Chatterjee ; Christopher L Shaffer

Alcohol use disorders (AUDs) impact millions of individuals and there remain few effective treatment strategies. Despite evidence that neuronal nicotinic acetylcholine receptors (nAChRs) have a role in AUDs, it has not been established which subtypes of the nAChR are involved. Recent human genetic association studies have implicated the gene cluster CHRNA3-CHRNA5-CHRNB4 encoding the α3, α5, and β4 subunits of the nAChR in susceptibility to develop nicotine and alcohol dependence; however, their role in ethanol-mediated behaviors is unknown due to the lack of suitable and selective research tools. To determine the role of the α3, and β4 subunits of the nAChR in ethanol self-administration, we developed and characterized high-affinity partial agonists at α3β4 nAChRs, CP-601932, and PF-4575180. Both CP-601932 and PF-4575180 selectively decrease ethanol but not sucrose consumption and operant self-administration following long-term exposure. We show that the functional potencies of CP-601932 and PF-4575180 at α3β4 nAChRs correlate with their unbound rat brain concentrations, suggesting that the effects on ethanol self-administration are mediated via interaction with α3β4 nAChRs. Also varenicline, an approved smoking cessation aid previously shown to decrease ethanol consumption and seeking in rats and mice, reduces ethanol intake at unbound brain concentrations that allow functional interactions with α3β4 nAChRs. Furthermore, the selective α4β2(*) nAChR antagonist, DHβE, did not reduce ethanol intake. Together, these data provide further support for the human genetic association studies, implicating CHRNA3 and CHRNB4 genes in ethanol-mediated behaviors. CP-601932 has been shown to be safe in humans and may represent a potential novel treatment for AUDs.

100 Deals associated with CP-601932

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Indication	Highest Phase	Country/Location	Organization	Date
Behavioural disorders	Phase 2	-	Pfizer Inc.	-

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