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      Biological redundancy of endogenous GPCR ligands in the gut and the potential for endogenous functional selectivity

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          Abstract

          This review focuses on the existence and function of multiple endogenous agonists of the somatostatin and opioid receptors with an emphasis on their expression in the gastrointestinal tract. These agonists generally arise from the proteolytic cleavage of prepropeptides during peptide maturation or from degradation of peptides by extracellular or intracellular endopeptidases. In other examples, endogenous peptide agonists for the same G protein-coupled receptors can be products of distinct genes but contain high sequence homology. This apparent biological redundancy has recently been challenged by the realization that different ligands may engender distinct receptor conformations linked to different intracellular signaling profiles and, as such the existence of distinct ligands may underlie mechanisms to finely tune physiological responses. We propose that further characterization of signaling pathways activated by these endogenous ligands will provide invaluable insight into the mechanisms governing biased agonism. Moreover, these ligands may prove useful in the design of novel therapeutic tools to target distinct signaling pathways, thereby favoring desirable effects and limiting detrimental on-target effects. Finally we will discuss the limitations of this area of research and we will highlight the difficulties that need to be addressed when examining endogenous bias in tissues and in animals.

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          Most cited references139

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          Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone.

          A peptide has been isolated from ovine hypothalamus which, at 1 x 10(-9)M, inhibits secretion in vitro of immunoreactive rat or human growth hormones and is similarly active in vivo in rats. Its structure is H-Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys-OH The synthetic replicate is biologically active.
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            Signalling bias in new drug discovery: detection, quantification and therapeutic impact.

            Agonists of seven-transmembrane receptors, also known as G protein-coupled receptors (GPCRs), do not uniformly activate all cellular signalling pathways linked to a given seven-transmembrane receptor (a phenomenon termed ligand or agonist bias); this discovery has changed how high-throughput screens are designed and how lead compounds are optimized for therapeutic activity. The ability to experimentally detect ligand bias has necessitated the development of methods for quantifying agonist bias in a way that can be used to guide structure-activity studies and the selection of drug candidates. Here, we provide a viewpoint on which methods are appropriate for quantifying bias, based on knowledge of how cellular and intracellular signalling proteins control the conformation of seven-transmembrane receptors. We also discuss possible predictions of how biased molecules may perform in vivo, and what potential therapeutic advantages they may provide.
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              Operational models of pharmacological agonism.

              The traditional receptor-stimulus model of agonism began with a description of drug action based on the law of mass action and has developed by a series of modifications, each accounting for new experimental evidence. By contrast, in this paper an approach to modelling agonism is taken that begins with the observation that experimental agonist-concentration effect, E/[A], curves are commonly hyperbolic and develops using the deduction that the relation between occupancy and effect must be hyperbolic if the law of mass action applies at the agonist-receptor level. The result is a general model that explicitly describes agonism by three parameters: an agonist-receptor dissociation constant, KA; the total receptor concentration, [R0]; and a parameter, KE, defining the transduction of agonist-receptor complex, AR, into pharmacological effect. The ratio, [R0]/KE, described here as the 'transducer ratio', tau, is a logical definition for the efficacy of an agonist in a system. The model may be extended to account for non-hyperbolic E/[A] curves with no loss of meaning. Analysis shows that an explicit formulation of the traditional receptor-stimulus model is one particular form of the general model but that it is not the simplest. An alternative model is proposed, representing the cognitive and transducer functions of a receptor, that describes agonist action with one fewer parameter than the traditional model. In addition, this model provides a chemical definition of intrinsic efficacy making this parameter experimentally accessible in principle. The alternative models are compared and contrasted with regard to their practical and conceptual utilities in experimental pharmacology.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                28 November 2014
                2014
                : 5
                : 262
                Affiliations
                [1] 1Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences Parkville, VIC, Australia
                [2] 2Department of Anatomy and Neuroscience, The University of Melbourne Parkville, VIC, Australia
                Author notes

                Edited by: Dominique Massotte, Institut des Neurosciences Cellulaires et Intégratives, France

                Reviewed by: Jakub Fichna, Medical University of Lodz, Poland; Pamela J. Hornby, Johnson & Johnson, USA

                *Correspondence: Daniel P. Poole, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville, VIC 3052, Australia e-mail: daniel.poole@ 123456monash.edu

                This article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology.

                Article
                10.3389/fphar.2014.00262
                4246669
                25506328
                f38f9c9e-9a09-44c6-90ae-2add1ae8f4aa
                Copyright © 2014 Thompson, Canals and Poole.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 29 September 2014
                : 12 November 2014
                Page count
                Figures: 1, Tables: 2, Equations: 0, References: 145, Pages: 12, Words: 0
                Categories
                Pharmacology
                Review Article

                Pharmacology & Pharmaceutical medicine
                biased agonism,enteric nervous system,g protein-coupled receptor,somatostatin,somatostatin receptor,opioid,opioid receptor

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