☆ 4.7 Article

State-dependent alterations in sleep/wake architecture elicited by the M4 PAM VU0467154-Relation to antipsychotic-like drug effects

NEUROPHARMACOLOGY (2016)

Journal

NEUROPHARMACOLOGY

Volume 102, Issue -, Pages 244-253

Publisher

PERGAMON-ELSEVIER SCIENCE LTD

DOI: 10.1016/j.neuropharm.2015.11.016

Keywords

VU0467154; M-4 muscarinic acetylcholine receptor; Positive allosteric modulator; Electroencephalography; Clozapine; Xanomeline

Funding

AstraZeneca
Bristol Myers Squibb

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Abstract

Accumulating evidence indicates direct relationships between sleep abnormalities and the severity and prevalence of other symptom clusters in schizophrenia. Assessment of potential state-dependent alterations in sleep architecture and arousal relative to antipsychotic-like activity is critical for the development of novel antipsychotic drugs (APDs). Recently, we reported that VU0467154, a selective positive allosteric modulator (PAM) of the M-4 muscarinic acetylcholine receptor (mAChR), exhibits robust APD-like and cognitive enhancing activity in rodents. However, the state-dependent effects of VU0467154 on sleep architecture and arousal have not been examined. Using polysomnography and quantitative electroencephalographic recordings from subcranial electrodes in rats, we evaluated the effects of VU0467154, in comparison with the atypical APD clozapine and the M-1/M-4-preferring mAChR agonist xanomeline. VU0467154 induced state-dependent alterations in sleep architecture and arousal including delayed Rapid Eye Movement (REM) sleep onset, increased cumulative duration of total and Non-Rapid Eye Movement (NREM) sleep, and increased arousal during waking periods. Clozapine decreased arousal during wake, increased cumulative NREM, and decreased REM sleep. In contrast, xanomeline increased time awake and arousal during wake, but reduced slow wave activity during NREM sleep. Additionally, in combination with the N-methyl-D-aspartate subtype of glutamate receptor (NMDAR) antagonist MK-801, modeling NMDAR hypofunction thought to underlie many symptoms in schizophrenia, both VU0467154 and clozapine attenuated MK-801-induced elevations in high frequency gamma power consistent with an APD-like mechanism of action. These findings suggest that selective M-4 PAMs may represent a novel mechanism for treating multiple symptoms of schizophrenia, including disruptions in sleep architecture without a sedative profile. (c) 2015 Elsevier Ltd. All rights reserved.

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Design, synthesis and evaluation of novel 2-phenyl-3-(1H-pyrazol-4-yl) pyridine positive allosteric modulators for the M4 mAChR

Manuela Jorg, Emma T. van der Westhuizen, Yao Lu, K. H. Christopher Choy, David M. Shackleford, Elham Khajehali, Andrew B. Tobin, David M. Thal, Ben Capuano, Arthur Christopoulos, Celine Valant, Peter J. Scammells

Summary: The synthesis and comprehensive pharmacological evaluation of M4 mAChR PAMs structurally related to 1e, Me-C-c, [11C]MK-6884 and [18F]12 were reported. Small structural changes to the PAMs resulted in significant differences in baseline, potency, and maximum effect measures in cAMP assays compared to the endogenous ligand acetylcholine (ACh). The discovery of novel PAMs with improved allosteric properties, 6k and 6l, and their ability to cross the blood-brain barrier make them more suitable for future preclinical assessment.

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