The selectivity of drugs for G protein-coupled receptor (GPCR) signaling pathways is crucial for their therapeutic efficacy.Different agonists can cause receptors to recruit effector proteins at varying levels, thus inducing different signaling responses, called signaling bias.Although several GPCR-biased drugs are currently being developed, only a limited number of biased ligands have been identified regarding their signaling bias for the M1 muscarinic acetylcholine receptor (M1mAChR), and the mechanism is not yet well understood.In this study, we utilized bioluminescence resonance energy transfer (BRET) assays to compare the efficacy of six agonists in inducing Gαq and β-arrestin2 binding to M1mAChR.Our findings reveal notable variations in agonist efficacy in the recruitment of Gαq and β-arrestin2.Pilocarpine preferentially promoted the recruitment of β-arrestin2 (ΔΔRAi = -0.5), while McN-A-343 (ΔΔRAi = 1.5), Xanomeline (ΔΔRAi = 0.6), and Iperoxo (ΔΔRAi = 0.3) exhibited a preference for the recruitment of Gαq.We also used com. methods to verify the agonists and obtained consistent results.Mol. docking revealed that certain residues (e.g., Y404, located in TM7 of M1mAChR) could play crucial roles in Gαq signaling bias by interacting with McN-A-343, Xanomeline, and Iperoxo, whereas other residues (e.g., W378 and Y381, located in TM6) contributed to β-arrestin recruitment by interacting with Pilocarpine.The preference of activated M1mAChR for different effectors may be due to significant conformational changes induced by biased agonists.By characterizing bias towards Gαq and β-arrestin2 recruitment, our study provides insights into M1mAChR signaling bias.

01 May 2021·Life SciencesQ3 · MEDICINE

McN-A-343, a muscarinic agonist, reduces inflammation and oxidative stress in an experimental model of ulcerative colitis

Q3 · MEDICINE

Article

Author: Sousa, Stefany Guimarães ; Havt, Alexandre ; Vasconcelos, Daniel Fernando Pereira ; Batista, Jalles Arruda ; Ferreira, Francisco Cleber Silva ; de Oliveira, Jefferson Soares ; Bezerra, Nayonara Lanara Sousa Dutra ; Magalhães, Diva de Aguiar ; Pereira, Cynthia Maria Carvalho ; de Albuquerque, Ieda Figueira ; Monteiro, Carlos Eduardo da Silva ; da Costa Filho, Humberto Barbosa ; Soares, Pedro Marcos Gomes ; da Rocha Rodrigues, Lauanda ; Franco, Alvaro Xavier ; Di Lenardo, David ; Ferreira, Jayro Dos Santos ; Barbosa, André Luiz Dos Reis ; do Nascimento Lima, José Victor

AIMThe aim of the present study was to investigate the anti-inflammatory response mediated of the M1 muscarinic acetylcholine receptor (mAChR) during experimental colitis.MATERIAL AND METHODSAfter the induction of 6% acetic acid colitis, mice were treated with McN-A-343 0.5, 1.0, and 1.5 mg/kg or dexamethasone (DEXA, 2.0 mg/kg) or pirenzepine (PIR, 10 mg/kg; M1 mAChR antagonist). Colonic inflammation was assessed by macroscopic and microscopic lesion scores, colonic wet weight, myeloperoxidase (MPO) activity, interleukin-1 beta (IL1-β) levels and tumor necrosis factor alpha (TNF-α), glutathione (GSH), malondialdehyde (MDA) and nitrate and nitrite (NO₃/NO₂), mRNA expression of IKKα, nuclear factor kappa beta (NF-kB) and cyclooxygenase-2 (COX-2), as well protein expression of NF-kB and COX-2.RESULTSTreatment with McN-A-343 at a concentration of 1.5 mg/kg showed a significant reduction in intestinal damage as well as a decrease in wet weight, MPO activity, pro-inflammatory cytokine concentration, markers of oxidative stress and expression of inflammatory mediators. The action of the M1 agonist by the administration of pirenzepine, which promoted the blocking of the mAChR M1-mediated anti-inflammatory response, has also been proven.CONCLUSIONThe results suggest that peripheral colonic M1 mAChR is involved in reversing the pro-inflammatory effect of experimentally induced colitis, which may represent a promising therapeutic alternative for patients with ulcerative colitis.

01 Aug 2020·Experimental Biology and MedicineQ4 · MEDICINE

The M1 muscarinic acetylcholine receptor in the crypt stem cell compartment mediates intestinal mucosal growth

Q4 · MEDICINE

Article

Author: Greig, Chasen J ; Armenia, Sarah J ; Cowles, Robert A

Maintenance of the highly plastic intestinal epithelium relies upon stem cells localized to intestinal crypts. Recent evidence suggests muscarinic acetylcholine signaling impacts epithelial barrier function, proliferation, and apoptosis. We hypothesized that the intestinal crypt base would express specific muscarinic acetylcholine receptors that drive proliferation in this critical region. Intestinal segments spanning the small bowel were procured from wild-type C57Bl/6 mice to determine muscarinic acetylcholine receptor mRNA expression and create sections on laser capture microdissection slides for analysis of crypt base cells. RT-PCR was performed using primers targeting the five muscarinic acetylcholine receptor subtypes (M1–M5), LGR5, BIII-tubulin, and GAPDH. To determine the effects of muscarinic agonism in vivo, osmotic pumps delivering the M1 muscarinic acetylcholine receptor agonist McN-A-343 were implanted into wild type mice for one week. Segments were harvested, histologic sections created, and morphometric and proliferative parameters measured. In full-thickness intestinal samples, muscarinic acetylcholine receptor subtypes M1–M4 were found in all regions, while M5 was localized to the proximal jejunum. In crypt-base cells, the M1 muscarinic acetylcholine receptor subtype was the only subtype found and was present in all regions. LGR5 was present in all laser capture microdissection samples, indicating the capture of intestinal stem cells. In vivo experiments conducted with McN-A-343 revealed significantly increased villus height, crypt depth, and crypt-cell proliferation. The presence of M1 muscarinic acetylcholine receptor mRNA within the stem cell niche in the intestinal crypt base coupled with increased mucosal growth with M1 receptor stimulation in vivo suggests that the cholinergic system, via the M1 muscarinic acetylcholine receptor, is a critical mediator of intestinal mucosal homeostasis. Impact statement Localization of a specific subtype of the muscarinic acetylcholine receptor in the crypt stem cell compartment suggests a critical role in intestinal mucosal homeostasis. Here we demonstrate the localization of the M1 muscarinic acetylcholine receptor to the stem cell compartment and demonstrate increase morphometric and proliferative parameters when this is stimulated in vivo. These data provide novel information about this complex signaling microenvironment and offer potential future therapeutic targets for future study.

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Alzheimer Disease	Discovery	US	McNeil Technologies, Inc.	-

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