AbstractMuscarinic acetylcholine receptors (mAChRs) have been shown to mediate alcohol consumption and seeking. Both M4 and M5 mAChRs have been highlighted as potential novel treatment targets for alcohol use disorders (AUD). Similarly, M1 mAChRs are expressed throughout reward circuitry, and their signaling has been implicated in cocaine consumption. However, whether the same effects are seen for alcohol consumption, or whether natural reward intake is inadvertently impacted is still unknown. To determine the role of M1 mAChRs in alcohol consumption, we tested operant self‐administration of alcohol under both fixed ratio (FR3) and progressive ratio (PR3‐4) schedules. Enhancing M1 mAChR signaling (via the M1 PAM‐Agonist PF‐06767832, 1 mg/kg, i.p.) reduced operant alcohol consumption on a fixed schedule but had no effect on motivation to acquire alcohol. To determine whether these actions were specific to alcohol, we examined the effects of M1 enhancement on natural reward (sucrose) self‐administration. Systemic administration of PF‐06767832 (1 mg/kg, i.p.) also reduced operant sucrose self‐administration, suggesting the actions of the M1 receptor may be non‐selective across drug and natural rewards. Finally, to understand whether this reduction extended to natural consummatory behaviors, we assessed home cage standard chow and water consumption. M1 enhancement via systemic PF‐06767832 administration reduced food and water consumption. Together our results suggest the M1 PAM‐agonist, PF‐06767832, non‐specifically reduces consummatory behaviors that are not associated with motivational strength for the reward. These data highlight the need to further characterize M1 agonists, PAMs, and PAM‐agonists, which may have varying degrees of utility in the treatment of neuropsychiatric disorders including AUD.

01 Aug 2018·Biochemical PharmacologyQ2 · MEDICINE

Probing the binding site of novel selective positive allosteric modulators at the M1 muscarinic acetylcholine receptor

Q2 · MEDICINE

Article

Author: Jörg, Manuela ; Sexton, Patrick M ; Lindsley, Craig W ; Conn, P Jeffrey ; Valant, Celine ; Khajehali, Elham ; Christopoulos, Arthur ; Scammells, Peter J ; Tobin, Andrew B

Subtype-selective allosteric modulation of the M₁ muscarinic acetylcholine (ACh) receptor (M₁ mAChR) is an attractive approach for the treatment of numerous disorders, including cognitive deficits. The discovery of benzyl quinolone carboxylic acid, BQCA, a selective M₁ mAChR positive allosteric modulator (PAM), spurred the subsequent development of newer generation M₁ PAMs representing diverse chemical scaffolds, different pharmacodynamic properties and, in some instances, improved pharmacokinetics. Key exemplar molecules from such efforts include PF-06767832 (N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-5-methyl-4-(4-(thiazol-4-yl)benzyl)pyridine-2-carboxamide), VU6004256 (4,6-difluoro-N-(1S,2S)-2-hydroxycyclohexyl-1-((6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-yl)methyl)-1H-indole-3-carboxamide) and MIPS1780 (3-(2-hydroxycyclohexyl)-6-(2-((4-(1-methyl-1H-pyrazol-4-yl)-benzyl)oxy)phenyl)pyrimidin-4(3H)-one). Given these diverse scaffolds and pharmacodynamics, the current study combined pharmacological analysis and site-directed mutagenesis to explore the potential binding site and function of newer M₁ mAChR PAMs relative to BQCA. Interestingly, the mechanism of action of the novel PAMs was consistent with a common model of allostery, as previously described for BQCA. Key residues involved in the activity of BQCA, including Y179 in the second extracellular loop (ECL) and W400^7.35 in transmembrane domain (TM) 7, were critical for the activity of all PAMs tested. Overall, our data indicate that structurally distinct PAMs share a similar binding site with BQCA, specifically, an extracellular allosteric site defined by residues in TM2, TM7 and ECL2. These findings provide valuable insights into the structural basis underlying modulator binding, cooperativity and signaling at the M₁ mAChR, which is essential for the rational design of PAMs with tailored pharmacological properties.

14 Jul 2016·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of the Potent and Selective M1 PAM-Agonist N-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-5-methyl-4-[4-(1,3-thiazol-4-yl)benzyl]pyridine-2-carboxamide (PF-06767832): Evaluation of Efficacy and Cholinergic Side Effects

Q1 · MEDICINE

Article

Author: Cordes, Jason ; Nason, Deane M. ; Lotarski, Susan M. ; Davoren, Jennifer E. ; Nottebaum, Lisa ; Northcott, Carrie ; Edgerton, Jeremy R. ; Mao, Yuxia ; Popiolek, Michael ; Brodney, Michael A. ; Lee, Che-Wah ; Salomon-Ferrer, Romelia ; Steyn, Stefanus J. ; Pettersen, Betty ; Lazzaro, John T. ; Harris, Anthony R. ; O'Neil, Steven V. ; Reinhart, Veronica ; Dlugolenski, Keith ; Kauffman, Gregory W. ; Webb, Damien ; Kenakin, Terrence P. ; Garnsey, Michelle ; Grimwood, Sarah ; Jenkinson, Stephen ; Helal, Christopher J. ; Zhang, Lei

It is hypothesized that selective muscarinic M1 subtype activation could be a strategy to provide cognitive benefits to schizophrenia and Alzheimer's disease patients while minimizing the cholinergic side effects observed with nonselective muscarinic orthosteric agonists. Selective activation of M1 with a positive allosteric modulator (PAM) has emerged as a new approach to achieve selective M1 activation. This manuscript describes the development of a series of M1-selective pyridone and pyridine amides and their key pharmacophores. Compound 38 (PF-06767832) is a high quality M1 selective PAM that has well-aligned physicochemical properties, good brain penetration and pharmacokinetic properties. Extensive safety profiling suggested that despite being devoid of mAChR M2/M3 subtype activity, compound 38 still carries gastrointestinal and cardiovascular side effects. These data provide strong evidence that M1 activation contributes to the cholinergic liabilities that were previously attributed to activation of the M2 and M3 receptors.

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