Discovery of 4-(5-Methyloxazolo[4,5-<i>b</i>]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (CP-810,123), a Novel α7 Nicotinic Acetylcholine Receptor Agonist for the Treatment of Cognitive Disorders in Schizophrenia: Synthesis, SAR Development, and in Vivo Efficacy in Cognition Models

O’Donnell, Christopher J; Rogers, Bruce N.; Bronk, Brian S.; Bryce, Dianne K.; Coe, Jotham W.; Cook, Karen K.; Duplantier, Allen J.; Evrard, Edelweiss; Hajós, Mihály; Hoffmann, William E.; Hurst, Raymond S; Maklad, Noha; Mather, Robert J.; McLean, Stafford; Nedza, Frank M.; O’Neill, Brian T.; Peng, Langu; Qian, Weimin; Rottas, Melinda M.; Sands, Steven B.; Schmidt, Anne W.; Shrikhande, Alka; Spracklin, Douglas K.; Wong, Diane; Zhang, Andy; Zhang, Lei

doi:10.1021/jm9015075

Cited by 69 publications

(30 citation statements)

References 65 publications

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“…Since this effect was blocked by MLA, it was hypothesized that EVP-6124 could improve cognition in patients with memory disorders, such as schizophrenia. Finally, the orthosteric full agonist CP-810123 was noted to have high BBB permeability and bioavailability, and reversed amphetamine-induced disruption in sensory gating as well as scopolamine-induced disruption of 30-min delayed NORT in rats [176]. Thus, there is increasing preclinical evidence of novel orthosteric ligands that may improve some of the behavioral abnormalities associated with schizophrenia.…”

Section: Ligands Their Targets and Putative Effects In Preclinicmentioning

confidence: 99%

Evaluating the role of the alpha-7 nicotinic acetylcholine receptor in the pathophysiology and treatment of schizophrenia

Young

Geyer

2013

Biochemical Pharmacology

115

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The group of schizophrenia disorders affects approximately 1% of the population and has both genetic and environmental etiologies. Sufferers report various behavioral abnormalities including hallucinations and delusions (positive symptoms), reduced joy and amotivation (negative symptoms), plus inattention and poor learning (cognitive deficits). Despite the heterogeneous symptoms experienced, most patients smoke. The self-medication hypothesis posits that patients smoke to alleviate symptoms, consistent with evidence for nicotine-induced enhancement of cognition. While nicotine acts on multiple nicotinic acetylcholine receptors (nAChRs), the primary target of research is often the homomeric α7 nAChR. Given genetic linkages between schizophrenia and this receptor, its association with P50 sensory gating deficits, and its reduced expression in post-mortem brains, many have attempted to develop α7 nAChR ligands for treating schizophrenia. Recent evidence that ligands can be orthosteric agonists or positive allosteric modulators (PAMs) has revitalized the hope for treatment discovery. Herein, we present evidence regarding: 1) Pathophysiological alterations of α7 nAChRs that might occur in patients; 2) Mechanistic evidence for the normal action of α7 nAChRs; 3) Preclinical studies using α7 nAChR orthosteric agonists and type I/II PAMs; and 4) Where successful translational testing has occurred for particular compounds, detailing what is still required. We report that the accumulating evidence is positive, but that greater work is required using positron emission tomography to understand current alterations in α7 nAChR expression and their relationship to symptoms. Finally, cross-species behavioral tasks should be used more regularly to determine the predictive efficacy of treatments.

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Section: Ligands Their Targets and Putative Effects In Preclinicmentioning

confidence: 99%

Evaluating the role of the alpha-7 nicotinic acetylcholine receptor in the pathophysiology and treatment of schizophrenia

Young

Geyer

2013

Biochemical Pharmacology

115

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“…This is a potent and selective agonist with high oral bioavailability and in vivo efficacy in auditory sensory gating and novel object recognition (O’Donnell et al 2010). Pfizer currently has two drugs in development.…”

Section: Initial Trials Of Nicotinic Agonists In Schizophreniamentioning

confidence: 99%

Nicotinic Mechanisms in the Treatment of Psychotic Disorders: A Focus on the α7 Nicotinic Receptor

Olincy

Freedman

2012

Novel Antischizophrenia Treatments

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Nicotine is heavily abused by persons with schizophrenia. Nicotine better enables people with schizophrenia to filter out extraneous auditory stimuli. Nicotine also improves prepulse inhibition when compared to placebo. Nicotine similarly increases the amplitude of patients’ duration mismatch negativity. The 15q13-14 region of the genome coding for the α7 nicotinic receptor is linked to schizophrenia. Multiple single nucleotide polymorphisms have been identified in this 15q13-14 gene promoter region that are more frequently present in people with schizophrenia than in normal controls. Abnormalities in expression and regulation of central nicotinic cholinoceptors with decreased α7 binding in multiple brain regions are also present. Nicotine enhances cognition in schizophrenia. Alternative agents that activate the nicotinic receptor have been tested including 3-[2,4-dimethoxybenzylidene]anabaseine (DMXB-A). This compound improved attention, working memory, and negative symptoms in an add-on study in non-smoking patients with schizophrenia. There are multiple other nicotinic agents, including positive allosteric modulators, in the preclinical stages of development. Finally, the effects of varenicline and clozapine and their relation to smoking cessation are discussed.

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“…Recently, O’Donnell et al. (70) explored the structure–activity relationship (in particular, probing the steric and electronic requirements) of benzoxazole and azabenzoxazole replacements of the carbamate functional group of a previous series (69) by substituent substitutions around the heteroaromatic ring system. A good balance of potency, selectivity, and high affinity agonist activity was found with CP‐810,123 (4‐(5‐Methyloxazoleo[4,5‐ b ]pyridin‐2‐yl)‐1,4‐diazabicyclo[3·2·2]nonane) (Fig.…”

Section: Selective Agonists/modulatorsmentioning

confidence: 99%

Cancer ‘survivor-care’: I. the α7 nAChR as potential target for chemotherapy-related cognitive impairment

Raffa¹

2010

Journal of Clinical Pharmacy and Therapeutics

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SUMMARY What is known and Objective Far more patients are now surviving cancer than ever before because of major advances in the diagnosis and treatment of primary and metastatic malignancy. Adjuvant chemotherapeutic drug and combination regimens have contributed to the success. However, persistent residual adverse effects involving mild impairment of cognitive impairment have been reported. Our objective is to review and to comment on the basic science and clinical evidence of potential pharmacologic targets for managing this emerging concern. Comment A search was conducted of basic science and clinical literature related to the objective and the information obtained was organized and evaluated from the perspective of its insight into potential pharmacotherapeutic targets. A large body of evidence suggests that the nicotinic acetylcholine receptor (nAChR), and in particular the α7 subtype, is involved in memory and that agonists and positive allosteric modulators of this receptor have potential in schizophrenia and Alzheimer animal models and patients. What is new and Conclusion We identify significant indirect evidence that the selective α7 nAChR drugs that are currently being investigated for cognitive improvement in schizophrenia and Alzheimer disease patients may be useful in cancer chemotherapy-related cognitive impairment. The clinical use of those drugs should be explored.

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Discovery of 4-(5-Methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (CP-810,123), a Novel α7 Nicotinic Acetylcholine Receptor Agonist for the Treatment of Cognitive Disorders in Schizophrenia: Synthesis, SAR Development, and in Vivo Efficacy in Cognition Models

Cited by 69 publications

References 65 publications

Evaluating the role of the alpha-7 nicotinic acetylcholine receptor in the pathophysiology and treatment of schizophrenia

Evaluating the role of the alpha-7 nicotinic acetylcholine receptor in the pathophysiology and treatment of schizophrenia

Nicotinic Mechanisms in the Treatment of Psychotic Disorders: A Focus on the α7 Nicotinic Receptor

Cancer ‘survivor-care’: I. the α7 nAChR as potential target for chemotherapy-related cognitive impairment

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