The Experts below are selected from a list of 243 Experts worldwide ranked by ideXlab platform
Terry Kenakin - One of the best experts on this subject based on the ideXlab platform.
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Receptor Theory.
Current protocols in pharmacology, 2020Co-Authors: Terry KenakinAbstract:Receptor Theory assigns mathematical rules to biological systems in order to quantify drug effects and define what biological systems can and cannot do, leading to the design of experiments that may further modify the model. Drug Receptor Theory also furnishes the tools for quantifying the activity of drugs in a system-independent manner, essential because drugs are almost always studied in test systems somewhat removed from the therapeutic system for which they are intended. Since biological systems operate at different set points in the body under different conditions, the ability to predict drug effects under a variety of circumstances is important. This unit provides a historical perspective of classical Receptor Theory and the currently used operational model of drug effects. The mechanism of drug Receptor function is also described in terms of the various iterations of the ternary complex model, the two-state Theory for ion channels, and a probabilistic model of multiple Receptor conformations.
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Principles: Receptor Theory in pharmacology
Trends in Pharmacological Sciences, 2004Co-Authors: Terry KenakinAbstract:Pharmacological Receptor Theory is discussed with special reference to advances made during the past 25 years. Thus, the operational model has supplanted analysis of drug-Receptor interaction in functional systems whereas the extended ternary complex model is used routinely to simulate quantitatively G-protein-coupled Receptor (GPCR) behavior. Six new behaviors for GPCRs, centered on spontaneous production of Receptor active states, ligand-selective Receptor active states, oligomerization with other proteins (Receptor and non-Receptor) and allosteric mechanisms, have been characterized and each holds the potential for new drug discovery for therapeutic benefit.
Hajime Asama - One of the best experts on this subject based on the ideXlab platform.
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pitchfork bifurcation in a Receptor Theory based model of the serotonergic system
Molecular BioSystems, 2013Co-Authors: Shiro Yano, Takayuki Watanabe, Hitoshi Aonuma, Hajime AsamaAbstract:Abnormalities in the serotonergic system are thought to be a potent cause of several mental diseases. Past research has shown that autoReceptors are the key component. It is thought that the autoReceptor constructs a negative feedback circuit on this system and realizes homeostatic control on its neural activity. This study is mainly organized from the above mentioned knowledge. In this paper, we construct two possible models of the serotonergic system based on Receptor Theory and provide some predictions for this system with each model. In the first model, we predict that the deficit of serotonin synthesis causes destabilization of the amount of autoReceptors; autoReceptors show an explosive increase if serotonin synthesis drops below a certain threshold value. In the second model, we indicate that the serotonergic system changes its stable property from a monostable one to a bistable one by certain factors. We clarify these factors and show that this changing process is named pitch-fork bifurcation. Additionally, we also suggest another notable phenomena which would appear when we consider a stochastic perturbation on the Receptor expressions. Lastly, we suggest some experimental ideas towards the verification of the validity of these models.
Craig W Lindsley - One of the best experts on this subject based on the ideXlab platform.
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G-protein-coupled Receptors: From classical modes of modulation to allosteric mechanisms
ACS Chemical Biology, 2008Co-Authors: Thomas M Bridges, Craig W LindsleyAbstract:Heterotrimeric G-protein-coupled Receptors (GPCRs) represent a large protein family responsible for mediating extracellular to intracellular signaling within a broad range of physiological contexts. Various conventional models have been used to describe their interactions with ligands and G-proteins. In recent years, however, numerous novel ligand-Receptor interactions not adequately addressed by classical Receptor Theory have been recognized. In addition to traditional orthosteric ligands, many GPCRs can bind allosteric ligands that modulate Receptor activity by interacting with distinct or overlapping Receptor sites. Such ligands include positive allosteric modulators, which have become the focus of pharmaceutical drug discovery programs and have gained the attention of a growing body of basic and translational researchers within the academic community. Here, we review the fundamental aspects of allosteric GPCR modulation by small-molecule ligands, with particular focus on the emerging position of positive allosteric modulators in modern drug discovery.
William P. Clarke - One of the best experts on this subject based on the ideXlab platform.
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Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity.
The International Journal of Neuropsychopharmacology, 2018Co-Authors: Kelly A. Berg, William P. ClarkeAbstract:: Constitutive Receptor activity/inverse agonism and functional selectivity/biased agonism are 2 concepts in contemporary pharmacology that have major implications for the use of drugs in medicine and research as well as for the processes of new drug development. Traditional Receptor Theory postulated that Receptors in a population are quiescent unless activated by a ligand. Within this framework ligands could act as agonists with various degrees of intrinsic efficacy, or as antagonists with zero intrinsic efficacy. We now know that Receptors can be active without an activating ligand and thus display "constitutive" activity. As a result, a new class of ligand was discovered that can reduce the constitutive activity of a Receptor. These ligands produce the opposite effect of an agonist and are called inverse agonists. The second topic discussed is functional selectivity, also commonly referred to as biased agonism. Traditional Receptor Theory also posited that intrinsic efficacy is a single drug property independent of the system in which the drug acts. However, we now know that a drug, acting at a single Receptor subtype, can have multiple intrinsic efficacies that differ depending on which of the multiple responses coupled to a Receptor is measured. Thus, a drug can be simultaneously an agonist, an antagonist, and an inverse agonist acting at the same Receptor. This means that drugs have an additional level of selectivity (signaling selectivity or "functional selectivity") beyond the traditional Receptor selectivity. Both inverse agonism and functional selectivity need to be considered when drugs are used as medicines or as research tools.
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effector pathway dependent relative efficacy at serotonin type 2a and 2c Receptors evidence for agonist directed trafficking of Receptor stimulus
Molecular Pharmacology, 1998Co-Authors: Kelly A. Berg, Saul Maayani, Joseph Goldfarb, Clare Scaramellini, Paul Leff, William P. ClarkeAbstract:There are many examples of a single Receptor coupling directly to more than one cellular signal transduction pathway. Although traditional Receptor Theory allows for activation of multiple cellular effectors by agonists, it predicts that the relative degree of activation of each effector pathway by an agonist (relative efficacy) must be the same. In the current experiments, we demonstrate that agonists at the human serotonin2A (5-HT2A) and 5-HT2CReceptors activate differentially two signal transduction pathways independently coupled to the Receptors [phospholipase C (PLC)-mediated inositol phosphate (IP) accumulation and phospholipase A2(PLA2)-mediated arachidonic acid (AA) release]. The relative efficacies of agonists differed depending on which signal transduction pathway was measured. Moreover, relative to 5-HT, some 5-HT2C agonists (e.g., 3-trifluoromethylphenyl-piperazine) preferentially activated the PLC-IP pathway, whereas others (e.g., lysergic acid diethylamide) favored the PLA2-AA pathway. In contrast, when two dependent responses were measured (IP accumulation and calcium mobilization), agonist relative efficacies were not different. These data strongly support the hypothesis termed “agonist-directed trafficking of Receptor stimulus” recently proposed by Kenakin [Trends Pharmacol Sci16:232–238 (1995)]. Concentration-response curves to 5-HT2C agonists were fit well by a three-state model of Receptor activation, suggesting that two active Receptor states may be sufficient to explain pathway-dependent agonist efficacy. Rational drug design that optimizes preferential effector activity within a group of Receptor-selective drugs holds the promise of increased selectivity in clinically useful agents.
Shiro Yano - One of the best experts on this subject based on the ideXlab platform.
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pitchfork bifurcation in a Receptor Theory based model of the serotonergic system
Molecular BioSystems, 2013Co-Authors: Shiro Yano, Takayuki Watanabe, Hitoshi Aonuma, Hajime AsamaAbstract:Abnormalities in the serotonergic system are thought to be a potent cause of several mental diseases. Past research has shown that autoReceptors are the key component. It is thought that the autoReceptor constructs a negative feedback circuit on this system and realizes homeostatic control on its neural activity. This study is mainly organized from the above mentioned knowledge. In this paper, we construct two possible models of the serotonergic system based on Receptor Theory and provide some predictions for this system with each model. In the first model, we predict that the deficit of serotonin synthesis causes destabilization of the amount of autoReceptors; autoReceptors show an explosive increase if serotonin synthesis drops below a certain threshold value. In the second model, we indicate that the serotonergic system changes its stable property from a monostable one to a bistable one by certain factors. We clarify these factors and show that this changing process is named pitch-fork bifurcation. Additionally, we also suggest another notable phenomena which would appear when we consider a stochastic perturbation on the Receptor expressions. Lastly, we suggest some experimental ideas towards the verification of the validity of these models.
