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Antinociceptive Effects of Potent, Selective and Brain Penetrant Muscarinic M 4 Positive Allosteric Modulators in Rodent Pain Models

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2020

Brain Res 2020 Jun 15;1737:146814. doi: 10.1016/j.brainres.2020.146814. Epub 2020 Mar 29.

Antinociceptive Effects of Potent, Selective and Brain Penetrant Muscarinic M 4 Positive Allosteric Modulators in Rodent Pain Models

SM Grauer;R Sanoja;D Poulin;H Rashid;N Jochnowitz;M Calhoun;D Zwilling;GB Varty;TW Rosahl;H Meziane;C Mittlelhaeuser;R Mazzola;J Morrow;SM Smith;D Henze;J Marcus

Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA. Charles River Laboratories, In Vivo Pharmacology, Montreal (PCS-MTL), 22022 Transcanadienne, Senneville, QC H9X 3R3, Canada. Merck & Co, Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. Institut Clinique de la Souris (ICS), 1 rue Laurent Fries, BP 10142, 67404 Illkirch Cedex, France.

Service type: Knockout mice

Abstract

Analgesic properties of orthosteric agonists of the muscarinic M4 receptor subtype have been documented in literature reports, with evidence from pharmacological and in vivo receptor knock out (KO) studies. Constitutive M4 receptor KO mice demonstrated an increased response in the formalin pain model, supporting this hypothesis. Two novel positive allosteric modulators (PAM) of the M4 receptor, Compounds 1 and 2, were characterized in rodent models of acute nociception. Results indicated decreased time spent on nociceptive behaviors in the mouse formalin model, and efficacy in the mouse tail flick assay. The analgesic-like effects of Compounds 1 and 2 were shown to be on target, as the compounds lacked any activity in constitutive M4 KO mice, while retaining activity in wild type control littermates. The analgesic-like effects of Compounds 1 and 2 were significantly diminished in KO mice that have selective deletion of the M4 receptor in neurons that co-express the dopaminergic D1 receptor subtype, suggesting a centrally-mediated effect on nociception. The opioid antagonist naloxone did not diminish the effect of Compound 1, indicating the effects of Compound 1 are not secondarily linked to opioid pathways. Compound 1 was evaluated in the rat, where it demonstrated analgesic-like effects in tail flick and a subpopulation of spinal nociceptive sensitive neurons, suggesting some involvement of spinal mechanisms of nociceptive modulation. These studies indicate that M4 PAMs may be a tractable target for pain management assuming an appropriate safety profile, and it appears likely that both spinal and supraspinal pathways may mediate the antinociceptive-like effects.

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