M1-positive allosteric modulators lacking agonist activity provide the optimal profile for enhancing cognition

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Abstract

Highly selective positive allosteric modulators (PAMs) of the M 1 subtype of muscarinic acetylcholine receptor have emerged as an exciting new approach for improving cognitive function in patients suffering from Alzheimer’s disease and schizophrenia. However, excessive activation of M 1 is known to induce seizure activity and have actions in the prefrontal cortex (PFC) that could impair cognitive function. We now report a series of pharmacological, electrophysiological, and behavioral studies in which we find that recently reported M 1 PAMs, PF-06764427 and MK-7622, have robust agonist activity in cell lines and agonist effects in the mouse PFC, and have the potential to overactivate the M 1 receptor and disrupt PFC function. In contrast, structurally distinct M 1 PAMs (VU0453595 and VU0550164) are devoid of agonist activity in cell lines and maintain activity dependence of M 1 activation in the PFC. Consistent with the previously reported effect of PF-06764427, the ago-PAM MK-7622 induces severe behavioral convulsions in mice. In contrast, VU0453595 does not induce behavioral convulsions at doses well above those required for maximal efficacy in enhancing cognitive function. Furthermore, in contrast to the robust efficacy of VU0453595, the ago-PAM MK-7622 failed to improve novel object recognition, a rodent assay of cognitive function. These findings suggest that in vivo cognition-enhancing efficacy of M 1 PAMs can be observed with PAMs lacking intrinsic agonist activity and that intrinsic agonist activity of M 1 PAMs may contribute to adverse effects and reduced efficacy in improving cognitive function.

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SELECTIVE LOSS OF CENTRAL CHOLINERGIC NEURONS IN ALZHEIMER'S DISEASE

P DAVIES (1976)

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Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia.

Charles W. Potter, Craig Mallinckrodt, David L. McKinzie … (2008)

There are significant unmet needs in the treatment of schizophrenia, especially for the treatment of cognitive impairment, negative syndrome, and cognitive function. Preclinical data suggest that agonists with selective affinity for acetylcholine muscarinic receptors provide a potentially new mechanism to treat schizophrenia. The authors studied xanomeline, a relatively selective muscarinic type 1 and type 4 (M(1) and M(4)) receptor agonist, to determine if this agent is effective in the treatment of schizophrenia. In this pilot study, the authors examined the efficacy of xanomeline on clinical outcomes in subjects with schizophrenia (N=20) utilizing a double-blind, placebo-controlled, 4-week treatment design. Outcome measures included the Positive and Negative Syndrome Scale (PANSS) for schizophrenia, the Brief Psychiatric Rating Scale (BPRS), the Clinical Global Impression (CGI) scale, and a test battery designed to measure cognitive function in patients with schizophrenia. Subjects treated with xanomeline did significantly better than subjects in the placebo group on total BPRS scores and total PANSS scores. In the cognitive test battery, subjects in the xanomeline group showed improvements most robustly in measures of verbal learning and short-term memory function. These results support further investigation of xanomeline as a novel approach to treating schizophrenia.

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Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease.

F Bymaster, N Cutler, Alexander H Shannon … (1997)

To evaluate the therapeutic effects of selective cholinergic replacement with xanomeline tartrate, an m1 and m4 selective muscarinic receptor (mAChR) agonist in patients with probable Alzheimer disease (AD). A 6-month, randomized, double-blind, placebo-controlled, parallel-group trial followed by a 1-month, single-blind, placebo washout. Outpatients at 17 centers in the United States and Canada. A total of 343 men and women at least 60 years of age with mild to moderate AD. Patients received 75, 150, or 225 mg (low, medium, and high doses) of xanomeline per day or placebo for 6 months. Scores on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), the Clinician's Interview-Based Impression of Change (CIBIC+), the Alzheimer's Disease Symptomatology Scale (ADSS), and the Nurses' Observational Scale for Geriatric Patients (NOSGER). A significant treatment effect existed for ADAS-Cog (high dose vs placebo; P < or = .05), and CIBIC+ (high dose vs placebo; P < or = .02). Treatment Emergent Signs and Symptoms analysis of the ADSS, which assesses behavioral symptoms in patients with AD, disclosed significant (P < or = .002) dose-dependent reductions in vocal outbursts, suspiciousness, delusions, agitation, and hallucinations. On end-point analysis, NOSGER, which assesses memory, instrumental activities of daily living, self-care, mood, social behavior, and disturbing behavior in the elderly, also showed a significant dose-response relationship (P < or = .02). In the high-dose arm, 52% of patients discontinued treatment because of adverse events; dose-dependent adverse events were predominantly gastrointestinal in nature. Syncope, defined as loss of consciousness and muscle tone, occurred in 12.6% of patients in the high-dose group. The observed improvements in ADAS-Cog and CIBIC+ following treatment with xanomeline provide the first evidence, from a large-scale, placebo-controlled clinical trial, that a direct-acting muscarinic receptor agonist can improve cognitive function in patients with AD. Furthermore, the dramatic and favorable effects on disturbing behaviors in AD suggest a novel approach for treatment of noncognitive symptoms.