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• W2913426593 abstract "G-protein–coupled receptors (GPCRs) are the largest family of transmembrane signaling proteins. In the gastrointestinal tract, GPCRs expressed by epithelial cells sense contents of the lumen, and GPCRs expressed by epithelial cells, myocytes, neurons, and immune cells participate in communication among cells. GPCRs control digestion, mediate digestive diseases, and coordinate repair and growth. GPCRs are the target of more than one third of therapeutic drugs, including many drugs used to treat digestive diseases. Recent advances in structural, chemical, and cell biology research have shown that GPCRs are not static binary switches that operate from the plasma membrane to control a defined set of intracellular signals. Rather, GPCRs are dynamic signaling proteins that adopt distinct conformations and subcellular distributions when associated with different ligands and intracellular effectors. An understanding of the dynamic nature of GPCRs has provided insights into the mechanism of activation and signaling of GPCRs and has shown opportunities for drug discovery. We review the allosteric modulation, biased agonism, oligomerization, and compartmentalized signaling of GPCRs that control digestion and digestive diseases. We highlight the implications of these concepts for the development of selective and effective drugs to treat diseases of the gastrointestinal tract. G-protein–coupled receptors (GPCRs) are the largest family of transmembrane signaling proteins. In the gastrointestinal tract, GPCRs expressed by epithelial cells sense contents of the lumen, and GPCRs expressed by epithelial cells, myocytes, neurons, and immune cells participate in communication among cells. GPCRs control digestion, mediate digestive diseases, and coordinate repair and growth. GPCRs are the target of more than one third of therapeutic drugs, including many drugs used to treat digestive diseases. Recent advances in structural, chemical, and cell biology research have shown that GPCRs are not static binary switches that operate from the plasma membrane to control a defined set of intracellular signals. Rather, GPCRs are dynamic signaling proteins that adopt distinct conformations and subcellular distributions when associated with different ligands and intracellular effectors. An understanding of the dynamic nature of GPCRs has provided insights into the mechanism of activation and signaling of GPCRs and has shown opportunities for drug discovery. We review the allosteric modulation, biased agonism, oligomerization, and compartmentalized signaling of GPCRs that control digestion and digestive diseases. We highlight the implications of these concepts for the development of selective and effective drugs to treat diseases of the gastrointestinal tract. G-protein–coupled receptors (GPCRs) are the largest family of transmembrane signaling proteins, with approximately 800 members in the human genome. GPCRs transmit information about the external environment to the interior of the cell and thereby control most physiologic and pathologic processes. Approximately half the GPCRs have a sensory function and mediate olfaction, taste, perception of light, and pheromone signaling. Other GPCRs detect hormones, neurotransmitters, and paracrine factors and mediate communication among cells. GPCRs are the target of more than one third of therapeutic drugs, which illustrates their importance in disease and therapy.1Hauser A.S. Attwood M.M. Rask-Andersen M. et al.Trends in GPCR drug discovery: new agents, targets and indications.Nat Rev Drug Discov. 2017; 16: 829Crossref PubMed Scopus (387) Google Scholar The importance, diversity, and complexity of GPCRs are illustrated by their role in digestion and as targets for digestive disease (Figure 1). GPCRs with sensory functions in the digestive tract include receptors of taste buds for sweet, bitter, and savory tastes,2Chaudhari N. Roper S.D. The cell biology of taste.J Cell Biol. 2010; 190: 285Crossref PubMed Scopus (395) Google Scholar receptors of enteroendocrine cells for amino acids and proteins,3Reimann F. Tolhurst G. Gribble Fiona M. G-protein–coupled receptors in intestinal chemosensation.Cell Metab. 2012; 15: 421-431Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar and receptors of colonocytes for luminal proteases.4Kong W. McConalogue K. Khitin L.M. et al.Luminal trypsin may regulate enterocytes through proteinase-activated receptor 2.Proc Natl Acad Sci U S A. 1997; 94: 8884-8889Crossref PubMed Scopus (0) Google Scholar GPCRs also sense the products of the microbiome. For instance, secondary bile acids, which are synthesized by bacteria in the colon, activate Takeda GPCR5 on enterochromaffin cells and enteric neurons to evoke peristalsis.5Alemi F. Poole D.P. Chiu J. et al.The receptor TGR5 mediates the prokinetic actions of intestinal bile acids and is required for normal defecation in mice.Gastroenterology. 2013; 144: 145-154Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar Takeda GPCR5 expressed by cutaneous sensory nerves has been implicated in cholestatic pruritus.6Abu-Hayyeh S. Ovadia C. Lieu T. et al.Prognostic and mechanistic potential of progesterone sulfates in intrahepatic cholestasis of pregnancy and pruritus gravidarum.Hepatology. 2016; 63: 1287-1298Crossref PubMed Scopus (36) Google Scholar, 7Alemi F. Kwon E. Poole D.P. et al.The TGR5 receptor mediates bile acid-induced itch and analgesia.J Clin Invest. 2013; 123: 1513-1530Crossref PubMed Scopus (162) Google Scholar GPCRs of epithelial cells, myocytes, enteric neurons, and immune cells participate in cell-to-cell communication in the digestive system. They include receptors for structurally diverse ligands, including biogenic amines (catecholamines, histamine, serotonin), eicosanoids, amino acid transmitters, purine nucleotides, and neuropeptides, peptide hormones, and proteins. Thus, GPCRs orchestrate digestion (secretion, motility, transport), control disease processes (diseases of motility, secretion, inflammation, pain), and regulate growth and repair. Drugs that activate or inhibit GPCRs are effective therapies for digestive diseases (Figure 1). Although the endogenous ligands of many GPCRs are known, there remain approximately 100 GPCRs with unidentified natural ligands. Some of these orphan GPCRs have roles in the digestive system. For example, the Mas-related GPCR (MRGPR) family is composed of approximately 40 orphan receptors expressed by primary sensory neurons and mast cells.8Solinski H.J. Gudermann T. Breit A. Pharmacology and signaling of MAS-related G protein-coupled receptors.Pharmacol Rev. 2014; 66: 570-597Crossref PubMed Scopus (61) Google Scholar MrgprX2 (human) or MrgprB2 (murine homologue) is expressed by mast cells and mediates antibody-independent responses to basic secretagogues, including drugs and peptides associated with pseudo-allergic reactions.9McNeil B.D. Pundir P. Meeker S. et al.Identification of a mast-cell–specific receptor crucial for pseudo-allergic drug reactions.Nature. 2015; 519: 237-241Crossref PubMed Scopus (0) Google Scholar Substance P (SP), a gut neuropeptide, can activate MrgprX2. Mast cells are in proximity to sensory nerves containing SP and calcitonin gene-related peptide in the intestine.10Stead R.H. Tomioka M. Quinonez G. et al.Intestinal mucosal mast cells in normal and nematode-infected rat intestines are in intimate contact with peptidergic nerves.Proc Natl Acad Sci U S A. 1987; 84: 2975-2979Crossref PubMed Google Scholar Therefore, neuropeptides and MrgprX2 might mediate the communication between sensory nerves and mast cells. Communication between sensory neurons and mast cells has been implicated in irritable bowel syndrome (IBS).11Barbara G. Stanghellini V. De Giorgio R. et al.Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome.Gastroenterology. 2004; 126: 693-702Abstract Full Text Full Text PDF PubMed Scopus (978) Google Scholar GPCRs share a conserved structure with 7 transmembrane domains, 3 extracellular and 3 intracellular loops, and extracellular (N-terminal) and intracellular (C-terminal) tails of varying sizes. GPCRs are grouped into 5 families based on structural and functional similarities. The rhodopsin family (class A) includes receptors for neurotransmitters, peptides, visual pigments, odorants, tastants, and pheromones. The secretin family (class B) is composed of receptors for polypeptide gut hormones, including glucagon, glucagon-like peptides, glucose-dependent insulinotropic polypeptide, secretin, vasoactive intestinal peptide, pituitary adenylate cyclase-activating polypeptide, and growth hormone-releasing hormone. The glutamate family (class C) includes metabotropic glutamate receptors, a calcium-sensing receptor, and γ-aminobutyric acid (GABA) B receptors. Adhesion family GPCRs possess a large extracellular N-terminus that is cleaved during activation. The frizzled family, which includes frizzled and smoothened proteins, is activated by lipo-glycoproteins of the Wnt family (frizzled) and hedgehog family (smoothened). All GPCR families are represented in the digestive system. This review highlights how recent advances in structural, chemical, and cellular biology research have provided an understanding of the mechanism of action of GPCRs. The traditional view that GPCRs are simple on and off switches that operate at the surface of cells to control a defined set of intracellular signals has been superseded by the realization that GPCRs are dynamic signaling proteins that can adopt different conformations and subcellular distributions, depending on the mechanisms of their activation.12Geppetti P. Veldhuis N.A. Lieu T. et al.G protein-coupled receptors: dynamic machines for signaling pain and itch.Neuron. 2015; 88: 635-649Abstract Full Text Full Text PDF PubMed Google Scholar One aspect of the dynamic nature of GPCRs was exposed using x-ray crystallography and cryo-electron microscopy to probe GPCR structures. These approaches provided information about the organization of transmembrane, loop, and tail domains and their association with agonists, antagonists, G proteins, β-arrestins (ARRBs), and other signaling effectors.13Liang Y.L. Khoshouei M. Deganutti G. et al.Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor.Nature. 2018; 561: 492-497Crossref PubMed Scopus (45) Google Scholar, 14Liang Y.L. Khoshouei M. Glukhova A. et al.Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex.Nature. 2018; 555: 121-125Crossref PubMed Scopus (92) Google Scholar, 15Rasmussen S.G. Choi H.J. Fung J.J. et al.Structure of a nanobody-stabilized active state of the beta(2) adrenoceptor.Nature. 2011; 469: 175-180Crossref PubMed Scopus (1087) Google Scholar, 16Rasmussen S.G. DeVree B.T. Zou Y. et al.Crystal structure of the beta2 adrenergic receptor-Gs protein complex.Nature. 2011; 477: 549-555Crossref PubMed Scopus (1810) Google Scholar, 17Shukla A.K. Westfield G.H. Xiao K. et al.Visualization of arrestin recruitment by a G-protein–coupled receptor.Nature. 2014; 512: 218-222Crossref PubMed Scopus (0) Google Scholar Limitations of structural studies of GPCRs include a requirement to stabilize receptors and signaling complexes by mutation, fusion to stabilizing proteins, or with single-domain antibodies (nano-bodies). Moreover, structural studies only provide snapshots of receptors frozen in time. However, structural analyses have shown that GPCRs adopt distinct conformations when bound to different agonists, antagonists, and intracellular effector and regulators. Two pharmacologic paradigms have emerged from an appreciation of the structural dynamism of GPCRs: allosteric modulation18Christopoulos A. Advances in G protein-coupled receptor allostery: from function to structure.Mol Pharmacol. 2014; 86: 463-478Crossref PubMed Scopus (120) Google Scholar and biased agonism.19Kenakin T. Functional selectivity and biased receptor signaling.J Pharmacol Exp Ther. 2011; 336: 296-302Crossref PubMed Scopus (334) Google Scholar Structural studies also have provided evidence that certain GPCRs exist as oligomers rather than as monomers.20Manglik A. Kruse A.C. Kobilka T.S. et al.Crystal structure of the micro-opioid receptor bound to a morphinan antagonist.Nature. 2012; 485: 321-326Crossref PubMed Scopus (818) Google Scholar, 21Wu H. Wacker D. Mileni M. et al.Structure of the human kappa-opioid receptor in complex with JDTic.Nature. 2012; 485: 327-332Crossref PubMed Scopus (609) Google Scholar A second component of the dynamic nature of GPCRs was discovered using biosensors, biophysical approaches, and advanced imaging to study the trafficking and signaling of GPCRs in subcellular micro-domains. These studies showed that GPCRs are motile signaling proteins that, at activation, can traffic from the cell surface to endosomes by dynamin- and clathrin-mediated endocytosis. GPCRs in endosomes can generate sustained signals in subcellular compartments (ie, compartmentalized signaling) that control physiologic and pathologic processes.22Irannejad R. Tomshine J.C. Tomshine J.R. et al.Conformational biosensors reveal GPCR signalling from endosomes.Nature. 2013; 495: 534-538Crossref PubMed Scopus (407) Google Scholar, 23Irannejad R. Tsvetanova N.G. Lobingier B.T. et al.Effects of endocytosis on receptor-mediated signaling.Curr Opin Cell Biol. 2015; 35: 137-143Crossref PubMed Google Scholar, 24Jensen D.D. Lieu T. Halls M.L. et al.Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief.Sci Transl Med. 2017; 9Crossref Scopus (45) Google Scholar, 25Jimenez-Vargas N.N. Pattison L.A. Zhao P. et al.Protease-activated receptor-2 in endosomes signals persistent pain of irritable bowel syndrome.Proc Natl Acad Sci U S A. 2018; 115: E7438-E7447Crossref PubMed Scopus (23) Google Scholar, 26Murphy J.E. Padilla B.E. Hasdemir B. et al.Endosomes: a legitimate platform for the signaling train.Proc Natl Acad Sci U S A. 2009; 106: 17615-17622Crossref PubMed Scopus (238) Google Scholar, 27Yarwood R.E. Imlach W.L. Lieu T. et al.Endosomal signaling of the receptor for calcitonin gene-related peptide mediates pain transmission.Proc Natl Acad Sci U S A. 2017; 114: 12309-12314Crossref PubMed Scopus (40) Google Scholar Thus, GPCRs in endosomes, rather than at the plasma membrane, might be a target for therapy.28Thomsen A.R.B. Jensen D.D. Hicks G.A. et al.Therapeutic targeting of endosomal G-protein–coupled receptors.Trends Pharmacol Sci. 2018; 39: 879-891Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar We discuss allosteric modulation, biased agonism, oligomerization, and compartmentalized signaling of GPCRs that control digestion and digestive diseases and consider the implications of these concepts for the development of drugs to treat gastrointestinal diseases. Allosteric modulators are drugs or endogenous molecules that fine-tune the ability of agonists to activate GPCRs. The challenge of developing drugs that are selective for a particular GPCR subtype illustrates the potential of allosteric modulation for drug discovery. A single endogenous ligand can activate several GPCRs (eg, acetylcholine activates 5 muscarinic receptors, M1–5Rs). These GPCR subtypes regulate processes within the digestive system and elsewhere. For example, studies in receptor knockout mice indicate that M1R and M3R regulate salivary secretion,29Gautam D. Heard T.S. Cui Y. et al.Cholinergic stimulation of salivary secretion studied with M1 and M3 muscarinic receptor single- and double-knockout mice.Mol Pharmacol. 2004; 66: 260-267Crossref PubMed Scopus (0) Google Scholar whereas M2R and M3R control intestinal smooth muscle contraction.30Matsui M. Motomura D. Fujikawa T. et al.Mice lacking M2 and M3 muscarinic acetylcholine receptors are devoid of cholinergic smooth muscle contractions but still viable.J Neurosci. 2002; 22: 10627-10632Crossref PubMed Google Scholar M1R, M4R, and M5R function in the central nervous system.31Thomsen M. Sorensen G. Dencker D. Physiological roles of CNS muscarinic receptors gained from knockout mice.Neuropharmacology. 2018; 136: 411-420Crossref PubMed Scopus (3) Google Scholar Because the binding sites for endogenous ligands (orthosteric sites; “right” or “proper” in Greek) are conserved between GPCR subtypes, it is challenging to identify subtype-selective drugs that occupy the same site as the natural ligand. An alternative approach to attain subtype selectivity is to develop drugs that bind to a different site (allosteric site; “other” in Greek).32Christopoulos A. Kenakin T. G protein-coupled receptor allosterism and complexing.Pharmacol Rev. 2002; 54: 323-374Crossref PubMed Scopus (0) Google Scholar, 33Monod J. Changeux J.P. Jacob F. Allosteric proteins and cellular control systems.J Mol Biol. 1963; 6: 306-329Crossref PubMed Google Scholar Ligands that interact with allosteric sites can induce changes in GPCR conformation that potentiate (positive allosteric modulators [PAMs]) or inhibit (negative allosteric modulators [NAMs]) endogenous agonists (Figure 2). Intracellular effectors, including G proteins and ARRBs, are physiologic allosteric modulators, because interaction with GPCRs induces changes in conformation that alter agonist affinity.34De Lean A. Stadel J.M. Lefkowitz R.J. A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled beta-adrenergic receptor.J Biol Chem. 1980; 255: 7108-7117Abstract Full Text PDF PubMed Google Scholar, 35Gurevich V.V. Pals-Rylaarsdam R. Benovic J.L. et al.Agonist-receptor-arrestin, an alternative ternary complex with high agonist affinity.J Biol Chem. 1997; 272: 28849-28852Crossref PubMed Scopus (139) Google Scholar There are advantages to drugs that interact with allosteric rather than orthosteric sites. First, allosteric modulators might provide subtype selectivity, because the allosteric site is likely to be less conserved than the orthosteric site, which evolved to bind the same endogenous transmitter. Second, allosteric ligands modulate the activity of GPCRs that are bound to endogenous ligands, providing an opportunity to fine-tune physiologic responses. Third, because the magnitude of an allosteric effect is limited by cooperativity between orthosteric and allosteric sites, allosteric ligands have a ceiling level beyond which no further modulation occurs, with decreased propensity for overdose and toxicity. These advantages have led to drug discovery efforts focused on the identification of allosteric modulators of GPCRs,18Christopoulos A. Advances in G protein-coupled receptor allostery: from function to structure.Mol Pharmacol. 2014; 86: 463-478Crossref PubMed Scopus (120) Google Scholar some of which have progressed to clinical trials.1Hauser A.S. Attwood M.M. Rask-Andersen M. et al.Trends in GPCR drug discovery: new agents, targets and indications.Nat Rev Drug Discov. 2017; 16: 829Crossref PubMed Scopus (387) Google Scholar However, there are only 2 approved allosteric modulators of GPCRs: maraviroc, a chemokine receptor 5 NAM that inhibits human immunodeficiency virus entry,36Dorr P. Westby M. Dobbs S. et al.Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity.Antimicrob Agents Chemother. 2005; 49: 4721-4732Crossref PubMed Scopus (825) Google Scholar and cinacalcet, a calcium-sensing receptor PAM used to treat hyperparathyroidism.37Block G.A. Martin K.J. de Francisco A.L. et al.Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis.N Engl J Med. 2004; 350: 1516-1525Crossref PubMed Scopus (864) Google Scholar These drugs were found to be allosteric modulators after regulatory approval. Consideration of the clinical utility of allosteric modulators of GPCRs raises 2 questions: are allosteric modulators a potential treatment for digestive diseases and will gastrointestinal-related adverse events prohibit use of PAMs and NAMs for non-gastrointestinal disorders? PAMs and NAMs have been developed for several GPCRs found in the gastrointestinal tract; some have progressed to clinical trials (Table 1).Table 1Clinical Trials of Allosteric Modulators, Biased Agonists, and Bivalent Ligands of GPCRs for Treatment of Disorders of the GI Tract or With Side Effects in the GI TractDrugMechanism of actionClinical indicationPotential GI effectOutcome of trialClinicalTrial.gov identifierAllosteric modulators MK-7622M1R PAMImproved cognition in Alzheimer diseaseDiarrheaTrial stopped for futility; diarrhea was most common side effectNCT01852110 ADX10059MGLUR5 NAMGERDDecreased refluxFurther testing stopped due to increased hepatic transaminasesNCT00820079Biased agonists TRV130MOR agonistPainDecreased nausea and vomiting; constipation not measured in trialsAnalgesia comparable to or better than morphineNCT02335294, NCT02083315 ADL5859DOR agonistPainPossible decreased effect on GI motility vs MOR agonist; however, not measured in trialNo analgesiaNCT00993863, NCT00626275, NCT00603265, NCT00979953 ADL5747DOR agonistPainPossible decreased effect on GI motility vs MOR agonist; however, not measured in trialNot effective for analgesiaNCT00979953, NCT01058642Oligomer targets EluxadolineMOR agonist and DOR antagonistIBS-D abdominal painAnalgesia for abdominal painApproved for clinical useNCT01553747, NCT01553591 EluxadolineMOR agonist and DOR antagonistIBS-D with bile acid malabsorptionImproved stool consistencyRecruitingNCT03441581 EluxadolineMOR agonist and DOR antagonistDiarrhea-associated fecal incontinenceFewer days with fecal incontinenceRecruitment pendingNCT03489265GI, gastrointestinal. Open table in a new tab GI, gastrointestinal. PAMs and NAMs have been identified for M1–5R.38Gentry P.R. Sexton P.M. Christopoulos A. Novel allosteric modulators of G protein-coupled receptors.J Biol Chem. 2015; 290: 19478-19488Crossref PubMed Scopus (90) Google Scholar Allosteric targeting of M1R, M4R, and M5R is an attractive treatment for disorders of the central nervous system, including schizophrenia, in which subtype-specificity would limit off-target effects on peripheral M2R and M3R, which are expressed in the digestive tract.39Conn P.J. Christopoulos A. Lindsley C.W. Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders.Nat Rev Drug Discov. 2009; 8: 41-54Crossref PubMed Scopus (691) Google Scholar The M1R PAM benzyl quinolone carboxylic acid alleviates cognitive deficits but induces diarrhea in mice.40Kurimoto E. Matsuda S. Shimizu Y. et al.An approach to discovering novel muscarinic M1 receptor positive allosteric modulators with potent cognitive improvement and minimized gastrointestinal dysfunction.J Pharmacol Exp Ther. 2018; 364: 28-37Crossref PubMed Scopus (2) Google Scholar, 41Thomsen M. Lindsley C.W. Conn P.J. et al.Contribution of both M1 and M4 receptors to muscarinic agonist-mediated attenuation of the cocaine discriminative stimulus in mice.Psychopharmacology (Berl). 2012; 220: 673-685Crossref PubMed Scopus (0) Google Scholar Compounds with differential positive cooperativity across subtypes could improve cognition with a lower risk of gastrointestinal side effects.42Sako Y. Kurimoto E. Mandai T. et al.TAK-071, a novel M1 positive allosteric modulator with low cooperativity, improves cognitive function in rodents with few cholinergic side effects.Neuropsychopharmacology. 2019; 44: 950-960Crossref PubMed Scopus (1) Google Scholar MK-7622, an M1R PAM, sensitizes M1R to acetylcholine in the nanomolar range with no effect on M2R, M3R, or M4R up to 100 μmol/L.43Uslaner J.M. Kuduk S.D. Wittmann M. et al.Preclinical to human translational pharmacology of the novel M1 positive allosteric modulator MK-7622.J Pharmacol Exp Ther. 2018; 365: 556-566Crossref PubMed Google Scholar MK-7622 improved cognitive testing in preclinical models. Two phase I trials tested MK-7622. MK-7622 produced an increase on the sigma band awake electroencephalogram, which indicated alertness. It also reversed the negative cognitive effects induced by scopolamine, a muscarinic receptor antagonist.43Uslaner J.M. Kuduk S.D. Wittmann M. et al.Preclinical to human translational pharmacology of the novel M1 positive allosteric modulator MK-7622.J Pharmacol Exp Ther. 2018; 365: 556-566Crossref PubMed Google Scholar Based on these results, a phase IIa and IIb, multicenter, randomized, double-blind, placebo-controlled, parallel group trial was undertaken to evaluate the efficacy and safety of MK-7622 as an adjunctive therapy to acetylcholinesterase inhibitors for Alzheimer disease (ClinicalTrials.gov, identifier NCT01852110). The trial was stopped because MK-7622 failed to improve cognition. Diarrhea, which is induced by acetylcholine, was the most common adverse event. Given the prominent role of M2R and M3R in regulating gastrointestinal smooth muscle, peripherally restricted allosteric modulators that fine-tune the actions of acetylcholine might offer a potential therapy for motility and secretory disturbances and visceral pain of IBS.44Wess J. Eglen R.M. Gautam D. Muscarinic acetylcholine receptors: mutant mice provide new insights for drug development.Nat Rev Drug Discov. 2007; 6: 721-733Crossref PubMed Scopus (410) Google Scholar Opioids and associated μ-, δ-, and κ-opioid receptors (μ-opioid receptor [MOR], δ-opioid receptor [DOR], and κ-opioid receptor, respectively) are expressed throughout the gut. In addition to their analgesic properties, which are mediated by opioid receptors (ORs) expressed by primary sensory neurons and second-order spinal neurons, opioids inhibit intestinal motility and electrolyte and fluid secretion by activating ORs on enteric neurons. Orthosteric agonists of MOR are used to treat pain (eg, morphine, fentanyl) and diarrhea (eg, loperamide). However, their usefulness is limited by respiratory depression, constipation, and addiction. Morphine-induced analgesia is limited by tolerance (ie, decreased effectiveness with sustained use). MOR PAMs could provide effective therapy without adverse effects by amplifying the actions of endogenous opioids or by allowing a decrease of the dose of synthetic opioids. BMS-986122 is a MOR PAM that potentiates opioids and morphine.45Burford N.T. Clark M.J. Wehrman T.S. et al.Discovery of positive allosteric modulators and silent allosteric modulators of the mu-opioid receptor.Proc Natl Acad Sci U S A. 2013; 110: 10830-10835Crossref PubMed Scopus (0) Google Scholar, 46Livingston K.E. Traynor J.R. Disruption of the Na+ ion binding site as a mechanism for positive allosteric modulation of the mu-opioid receptor.Proc Natl Acad Sci U S A. 2014; 111: 18369-18374Crossref PubMed Scopus (0) Google Scholar However, because respiratory depression and constipation are mediated by MOR, PAMs would be expected to potentiate these side effects. Although MOR is the prominent target of opioid analgesics, DOR also controls intestinal contractility.47DiCello J.J. Saito A. Rajasekhar P. et al.Inflammation-associated changes in DOR expression and function in the mouse colon.Am J Physiol Gastrointest Liver Physiol. 2018; 315: G544-G559Crossref PubMed Scopus (6) Google Scholar DOR is a target for diarrhea-predominant IBS (IBS-D),48Lembo A.J. Lacy B.E. Zuckerman M.J. et al.Eluxadoline for Irritable Bowel Syndrome with Diarrhea.N Engl J Med. 2016; 374: 242-253Crossref PubMed Google Scholar and enhancement of enkephalinergic signaling attenuates secretory diarrhea.49Turck D. Berard H. Fretault N. et al.Comparison of racecadotril and loperamide in children with acute diarrhoea.Aliment Pharmacol Ther. 1999; 13: 27-32PubMed Google Scholar BMS-986187 is a DOR PAM that amplifies the actions of DOR agonists.50Burford N.T. Livingston K.E. Canals M. et al.Discovery, synthesis, and molecular pharmacology of selective positive allosteric modulators of the delta-opioid receptor.J Med Chem. 2015; 58: 4220-4229Crossref PubMed Scopus (25) Google Scholar By modulating endogenous opioids, DOR PAMs have the potential to inhibit motility without causing constipation. Despite the promise of the MOR PAM (BMS-986122) and the DOR PAM (BMS-986187), the therapeutic potential of these drugs is yet to be assessed and they have not been tested in clinical trials. Allosteric modulators of gut GPCRs have been described for the treatment of other digestive disorders. Glutamate, a transmitter of visceral and somatic pain, can activate ionotropic receptors (ion channels) and metabotropic GPCRs (MGLUR1–8). MGLUR5, which is expressed by vagal afferent endings of the gastroesophageal sphincter, regulates sphincter tone, providing a basis for the development of allosteric modulators of MGLUR5 for gastroesophageal reflux disease (GERD). ADX10059 is a MGLUR5 NAM. A randomized, patient-blind, placebo-controlled trial demonstrated that ADX10059 decreased GERD-related symptoms.51Keywood C. Wakefield M. Tack J. A proof-of-concept study evaluating the effect of ADX10059, a metabotropic glutamate receptor-5 negative allosteric modulator, on acid exposure and symptoms in gastro-oesophageal reflux disease.Gut. 2009; 58: 1192-1199Crossref PubMed Scopus (0) Google Scholar Dizziness developed in 75% of participants. Then, ADX10059 was tested, at a lower dose, in a double-blind, placebo-controlled, multicenter trial in participants with proton pump inhibitor–responsive GERD. At this lower dose, ADX10059 increased symptom- and heartburn-free days and decreased regurgitation and sleep disturbance. Mild to moderate dizziness and vertigo were experienced by only 16% and 12% of patients, respectively52Zerbib F. Bruley des Varannes S. Roman S. et al.Randomised clinical trial: effects of monotherapy with ADX10059, a mGl" @default.
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• W2913426593 title "G-Protein–Coupled Receptors Are Dynamic Regulators of Digestion and Targets for Digestive Diseases" @default.
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