期刊
ACS CHEMICAL NEUROSCIENCE
卷 5, 期 10, 页码 920-942出版社
AMER CHEMICAL SOC
DOI: 10.1021/cn500128b
关键词
Allosteric modulator; antipsychotic; cognitive enhancement; M4 muscarinic; MK-801; VU0467154
资金
- National Institute of Mental Health [MH86601, MH87965]
- Psychiatric Center Copenhagen Research Foundation
- Carlsberg Foundation
- AstraZeneca
Positive allosteric modulators (PAMs) of the M-4 muscarinic acetylcholine receptor (mAChR) represent a novel approach for the treatment of psychotic symptoms associated with schizophrenia and other neuropsychiatric disorders. We recently reported that the selective M-4 PAM VU0152100 produced an antipsychotic drug-like profile in rodents after amphetamine challenge. Previous studies suggest that enhanced cholinergic activity may also improve cognitive function and reverse deficits observed with reduced signaling through the N-methyl-D-aspartate subtype of the glutamate receptor (NMDAR) in the central nervous system. Prior to this study, the M-1 mAChR subtype was viewed as the primary candidate for these actions relative to the other mAChR subtypes. Here we describe the discovery of a novel M-4 PAM, VU0467154, with enhanced in vitro potency and improved pharmacokinetic properties relative to other M-4 PAMs, enabling a more extensive characterization of M-4 actions in rodent models. We used VU0467154 to test the hypothesis that selective potentiation of M-4 receptor signaling could ameliorate the behavioral, cognitive, and neurochemical impairments induced by the noncompetitive NMDAR antagonist MK-801. VU0467154 produced a robust dose-dependent reversal of MK-801-induced hyperlocomotion and deficits in preclinical models of associative learning and memory functions, including the touchscreen pairwise visual discrimination task in wild-type mice, but failed to reverse these stimulant-induced deficits in M-4 KO mice. VU0467154 also enhanced the acquisition of both contextual and cue-mediated fear conditioning when administered alone in wild-type mice. These novel findings suggest that M-4 PAMs may provide a strategy for addressing the more complex affective and cognitive disruptions associated with schizophrenia and other neuropsychiatric disorders.
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