Effects and sites of action of a M1 receptor positive allosteric modulator on colonic motility in rats and dogs compared with 5‐HT4 agonism and cholinesterase inhibition

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 cause...

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Published in:Neurogastroenterology and motility 2020-08, Vol.32 (8), p.e13866-n/a
Main Authors: Tsukimi, Yasuhiro, Pustovit, Ruslan V., Harrington, Andrea M., Garcia‐Caraballo, Sonia, Brierley, Stuart M., Di Natale, Madeleine, Molero, Juan C., Furness, John B.
Format: Article
Language:English
Subjects:
Acetylcholine receptors (muscarinic)
Allosteric properties
Cholinesterase inhibitors
Colon
colonic motility
Constipation
Contraction
Defecation
Enteric nervous system
Epithelium
Hybridization
Ileum
Immunomodulation
Intestine
Lethal dose
Localization
muscarinic positive allosteric modulator
Neostigmine
Neuromodulation
prokinetics
prucalopride
Rodents
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Summary: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‐HT4 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. Left: in the colon, the M1 receptor is located to myenteric ganglia (mg) and the mucosal epithelium. Right: a maximally effective dose of an M1PAM causes strong colorectal propulsion, whereas the 5‐HT4 receptor agonist, prucalopride, and the cholinesterase inhibitor, neostigmine cause contractions that are less efficient in causing colorectal propulsion.
ISSN:1350-1925
1365-2982
DOI:10.1111/nmo.13866