Effects and sites of action of a M1 receptor positive allosteric modulator on colonic motility in rats and dogs compared with 5-HT 4 agonism and cholinesterase inhibition.

Autor: Tsukimi Y; Gastroenterology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Kanagawa, Japan., Pustovit RV; Florey Institute of Neuroscience and Mental Health, Parkville, Vic., Australia.; Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Vic., Australia., Harrington AM; Visceral Pain Research Group, Centre for Neuroscience, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia.; Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.; Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia., Garcia-Caraballo S; Visceral Pain Research Group, Centre for Neuroscience, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia.; Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.; Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia., Brierley SM; Visceral Pain Research Group, Centre for Neuroscience, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia.; Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.; Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia., Di Natale M; Florey Institute of Neuroscience and Mental Health, Parkville, Vic., Australia.; Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Vic., Australia., Molero JC; Florey Institute of Neuroscience and Mental Health, Parkville, Vic., Australia.; Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Vic., Australia., Furness JB; Florey Institute of Neuroscience and Mental Health, Parkville, Vic., Australia.; Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Vic., Australia.
Jazyk: angličtina
Zdroj: Neurogastroenterology and motility [Neurogastroenterol Motil] 2020 Aug; Vol. 32 (8), pp. e13866. Date of Electronic Publication: 2020 Apr 26.
DOI: 10.1111/nmo.13866
Abstrakt: Background: Muscarinic receptor 1 positive allosteric modulators (M1PAMs) enhance colonic propulsive contractions and defecation through the facilitation of M1 receptor (M1R)-mediated signaling. We examined M1R expression in the colons of 5 species and compared colonic propulsion and defecation caused by the M1PAM, T440, the 5-HT 4 agonist, prucalopride, and the cholinesterase inhibitor, neostigmine, in rats and dogs.
Methods: M1R expression was profiled by immunostaining and in situ hybridization. In vivo studies utilized male SD rats and beagle dogs. Colonic propulsive contractions were recorded by manometry in anesthetized rats. Gut contractions in dogs were assessed using implanted force transducers in the ileum, proximal, mid, and distal colons.
Key Results: M1R was localized to neurons of myenteric and submucosal plexuses and the epithelium of the human colon. A similar receptor localization was observed in rat, dog, mouse, and pig. T440 enhanced normal defecation in rats in a dose-dependent manner. Prucalopride also enhanced defecation in rats, but the maximum effect was half that of T440. Neostigmine and T440 were similarly effective in enhancing defecation, but the effective dose of neostigmine was close to its lethal dose. In rats, all 3 compounds induced colonic contractions, but the associated propulsion was strongest with T440. In dogs, intestinal contractions elicited by T440 propagated from ileum to distal colon. Prucalopride and neostigmine also induced intestinal contractions, but these were less well coordinated. No loss of effectiveness of T440 on defecation occurred after 5 days of repeated dosing.
Conclusion and Inferences: These results suggest that M1PAMs produce highly coordinated propagating contraction by actions on the enteric nervous system of the colon. The localization of M1R to enteric neurons in both animals and humans suggests that the M1PAM effects would be translatable to human. M1PAMs provide a potential novel therapeutic option for constipation disorders.
(© 2020 John Wiley & Sons Ltd.)
Databáze: MEDLINE
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