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Structure-Activity Relationships of Pan-G?q/11 Coupled Muscarinic Acetylcholine Receptor Positive Allosteric Modulators.

ABSTRACT: Recent years have seen a large increase in the discovery of allosteric ligands targeting muscarinic acetylcholine receptors (mAChRs). One of the challenges in screening such compounds is to understand their mechanisms of action and define appropriate parameter estimates for affinity, cooperativity and efficacy. Herein we describe the mechanisms of action and structure-activity relationships for a series of "pan-Gq-coupled" muscarinic acetylcholine (ACh) receptor (mAChR) positive allosteric modulators (PAMs). Using a combination of radioligand binding, functional inositol phosphate accumulation assays, receptor alkylation and operational data analysis, we show that most compounds in the series derive their variable potency and selectivity from differential cooperativity at the M1, M3 and M5 mAChRs. None of the PAMs showed greater than 10-fold subtype selectivity for the agonist-free receptor, but VU6007705, VU6007678, and VU6008555 displayed markedly increased cooperativity compared to the parent molecule and M5 mAChR-preferring PAM, ML380 (?? > 100), in the presence of ACh. Most of the activity of these PAMs derives from their ability to potentiate ACh binding affinity at mAChRs, though VU6007678 was notable for also potentiating ACh signaling efficacy and robust allosteric agonist activity. These data provide key insights for the future design of more potent and subtype-selective mAChR PAMs.

SUBMITTER: Berizzi AE

PROVIDER: S-EPMC6106869 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Publications

Structure-Activity Relationships of Pan-Gα<sub>q/11</sub> Coupled Muscarinic Acetylcholine Receptor Positive Allosteric Modulators.

Berizzi Alice E AE Bender Aaron M AM Lindsley Craig W CW Conn P Jeffrey PJ Sexton Patrick M PM Langmead Christopher J CJ Christopoulos Arthur A

ACS chemical neuroscience 20180430 7

Recent years have seen a large increase in the discovery of allosteric ligands targeting muscarinic acetylcholine receptors (mAChRs). One of the challenges in screening such compounds is to understand their mechanisms of action and define appropriate parameter estimates for affinity, cooperativity and efficacy. Herein we describe the mechanisms of action and structure-activity relationships for a series of "pan-G<sub>q</sub>-coupled" muscarinic acetylcholine (ACh) receptor (mAChR) positive allos ...[more]

PMID: 29683647

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Project description:Accumulating evidence suggests that selective M4 muscarinic acetylcholine receptor (mAChR) activators may offer a novel strategy for the treatment of psychosis. However, previous efforts to develop selective M4 activators were unsuccessful because of the lack of M4 mAChR subtype specificity and off-target muscarinic adverse effects. We recently developed VU0152100, a highly selective M4 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 M4 on region-specific brain activation, VU0152100 alone and in combination with amphetamine were evaluated using pharmacologic magnetic resonance imaging (phMRI). Key neural substrates of M4-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 M4 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 M4 PAMs as a new approach to the treatment of psychosis and cognitive impairments associated with psychiatric disorders such as schizophrenia.

Dataset Information

Structure-Activity Relationships of Pan-G?q/11 Coupled Muscarinic Acetylcholine Receptor Positive Allosteric Modulators.

Publications

Structure-Activity Relationships of Pan-Gα<sub>q/11</sub> Coupled Muscarinic Acetylcholine Receptor Positive Allosteric Modulators.

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