Antipsychotic Drug-Like Effects of the Selective M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0152100

Abstract

Accumulating evidence suggests that selective M 4 muscarinic acetylcholine receptor (mAChR) activators may offer a novel strategy for the treatment of psychosis. However, previous efforts to develop selective M 4 activators were unsuccessful because of the lack of M 4 mAChR subtype specificity and off-target muscarinic adverse effects. We recently developed VU0152100, a highly selective M 4 positive allosteric modulator (PAM) that exerts central effects after systemic administration. We now report that VU0152100 dose-dependently reverses amphetamine-induced hyperlocomotion in rats and wild-type mice, but not in M4 KO mice. VU0152100 also blocks amphetamine-induced disruption of the acquisition of contextual fear conditioning and prepulse inhibition of the acoustic startle reflex. These effects were observed at doses that do not produce catalepsy or peripheral adverse effects associated with non-selective mAChR agonists. To further understand the effects of selective potentiation of M 4 on region-specific brain activation, VU0152100 alone and in combination with amphetamine were evaluated using pharmacologic magnetic resonance imaging (phMRI). Key neural substrates of M 4 -mediated modulation of the amphetamine response included the nucleus accumbens (NAS), caudate-putamen (CP), hippocampus, and medial thalamus. Functional connectivity analysis of phMRI data, specifically assessing correlations in activation between regions, revealed several brain networks involved in the M 4 modulation of amphetamine-induced brain activation, including the NAS and retrosplenial cortex with motor cortex, hippocampus, and medial thalamus. Using in vivo microdialysis, we found that VU0152100 reversed amphetamine-induced increases in extracellular dopamine levels in NAS and CP. The present data are consistent with an antipsychotic drug-like profile of activity for VU0152100. Taken together, these data support the development of selective M 4 PAMs as a new approach to the treatment of psychosis and cognitive impairments associated with psychiatric disorders such as schizophrenia.

The muscarinic system, cognition and schizophrenia

“…The M4 receptor PAM VU0467154 was reported to exhibit an antipsychotic drug-like profile in mice, without inducing any side-effects associated with nonselective manipulation of peripheral muscarinic receptors . Likewise VU1052100, another M4 receptor PAM was also reported to express antipsychotic drug-like qualities through its capacity to reverse amphetamine-induced hypolocomotion in both rat and wild-type mice Byun et al, 2014). Furthermore, in two separate studies VU1052100 was unable to reverse amphetamine-and cocaine-induced hypolocomotion in M4-knockout mice, supporting the notion that M4 receptor agonism may produce antipsychotic drug-like effects via influencing dopaminergic signaling (Byun et al, 2014;Dencker et al, 2012).…”

Disruption of the Na + ion binding site as a mechanism for positive allosteric modulation of the mu-opioid receptor

“…Allosteric modulators have been discovered for several GPCRs including the muscarinic, cannabinoid, and metabotropic glutamate receptors (6-8) with a growing body of in vitro and in vivo literature describing allostery at GPCRs (9)(10)(11). In contrast, apart from our initial description of mu-PAMs, very little is known about allostery at MOPr.…”

Potentiation of M1 Muscarinic Receptor Reverses Plasticity Deficits and Negative and Cognitive Symptoms in a Schizophrenia Mouse Model

“…Although xanomeline failed to advance in clinical development because of peripheral adverse effects mediated by M 2 and M 3 activation, this compound had robust efficacy in reducing positive as well as negative symptoms and cognitive disturbances in schizophrenia patients. Extensive studies with novel, highly selective M 4 PAMs suggest that selective potentiation of M 4 has multiple effects in rodent models that predict efficacy in reducing positive symptoms (Byun et al, 2014;Chan et al, 2008). Thus, it is possible that activation of M 4 could play a dominant role in xanomeline's ability to reduce psychosis in schizophrenia patients, whereas M 1 may be more important in mediating xanomeline's efficacy in reducing negative and cognitive symptoms of schizophrenia.…”