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• W2805372544 endingPage "765" @default.
• W2805372544 startingPage "748" @default.
• W2805372544 abstract "PAM-antagonists exhibit a completely new profile of contradictory allosteric effects that confer a unique mode of antagonism. These molecules theoretical circumvent problems in overcoming persistent agonism and may be selectively more active in the presence of the agonist. PAM-antagonists may have unique properties with respect to long half-times for effect and target coverage in vivo. Seven transmembrane receptor (7TMR) responses are modulated by orthosteric and allosteric ligands to great therapeutic advantage. Here we introduce a unique class of negative allosteric modulator (NAM) – the positive allosteric modulator (PAM)-antagonist – that increases the affinity of the receptor for the agonist but concomitantly decreases agonist efficacy when cobound. Notably, the reciprocation of allosteric energy causes the orthosteric agonist to increase the affinity of the receptor for the PAM-antagonist; thus, this modulator seeks out and destroys agonist-bound receptor complexes. When contrasted with standard orthosteric and allosteric antagonists it is clear that PAM-antagonists are uniquely well suited to reversing ongoing persistent agonism and provide favorable target coverage in vivo. Specifically, the therapeutic application of PAM-antagonists to reverse pathological overactivation (e.g., endothelin vasoconstriction) is emphasized. Seven transmembrane receptor (7TMR) responses are modulated by orthosteric and allosteric ligands to great therapeutic advantage. Here we introduce a unique class of negative allosteric modulator (NAM) – the positive allosteric modulator (PAM)-antagonist – that increases the affinity of the receptor for the agonist but concomitantly decreases agonist efficacy when cobound. Notably, the reciprocation of allosteric energy causes the orthosteric agonist to increase the affinity of the receptor for the PAM-antagonist; thus, this modulator seeks out and destroys agonist-bound receptor complexes. When contrasted with standard orthosteric and allosteric antagonists it is clear that PAM-antagonists are uniquely well suited to reversing ongoing persistent agonism and provide favorable target coverage in vivo. Specifically, the therapeutic application of PAM-antagonists to reverse pathological overactivation (e.g., endothelin vasoconstriction) is emphasized. a fundamental property of GPCRs wherein agonists can disproportionately activate downstream GPCR signaling pathways (e.g., activating only certain G proteins and/or arrestins). Biased agonism is the result of ligands selecting from a diverse receptor conformational ensemble and stands in contrast to the classic two-state model positing that receptors are either ‘on’ or ‘off’, suggesting equal activation of all receptor-specific pathways (i.e., full agonists activate all pathways maximally). Biased signaling can be rationalized as probe dependence wherein agonist-bound receptors encounter different allosteric states of the receptor stabilized by different intracellular modulators (i.e., signal transduction molecules like G proteins and arrestins). in an allosteric system, the receptor simultaneously binds an agonist and a modulator at separate, nonoverlapping sites, which are referred to as ‘cobinding ligands’. the binding of agonist and antagonist is mutually exclusive because they compete for the same binding site. The receptor occupancies of the agonist and antagonist rapidly equilibrate and the relative occupancy of each ligand depends on its concentration and equilibrium dissociation constant. an incomplete kinetic state whereby an agonist, antagonist, and receptor are not in mass-action equilibrium, most often due to persistent antagonist binding in short-time-course assays (e.g., calcium release). Under these circumstances the agonist does not attain complete receptor occupancy to produce a maximal response and the agonist concentration–response curves have artificially depressed maxima. molar concentration of an antagonist that produces 50% inhibition of a predefined agonist response. an allosteric modulator may change the receptor to cause the endogenous agonist to become biased with respect to signaling compared with the signaling of the agonist before allosteric modulation. the equilibrium dissociation constant of the antagonist–receptor complex; also the concentration of antagonist that binds to 50% of the receptor population. a disorder resulting from an abnormality in a single defective gene on the autosome. this molecule binds to a separate allosteric site on the receptor to cause a reduction in the affinity/and or efficacy of the endogenous agonist to cause a reduction of agonist response. the receptor occupancies of the agonist and antagonist do not equilibrate according to the competitive antagonism equation due to the relatively slow offset (compared with the agonist) of the antagonist. Under these circumstances the ligands do not effectively compete but rather the response observed emanates only from non-antagonist-bound receptors; also termed ‘insurmountable antagonism’. the speed with which a bound molecule leaves (dissociates from) the receptor. It is determined by the offset rate constant, denoted k2 with unit s−1. the speed with which a given molecule associates with (binds to) a receptor. It is determined by the onset rate constant, denoted k1 with unit M−1s−1. this molecule binds to a separate allosteric site on the receptor and increases the affinity and/or the efficacy of the agonist to produce potentiation of an agonist response. a unique allosteric modulator that antagonizes agonist response by increasing the affinity of the receptor for the agonist (α > 1) but decreases its efficacy (β < 1), thereby making agonism overall less effective. These divergent allosteric effects promote a ‘seek-and-destroy’ mechanism of action. a probe of receptor function is any ligand that indicates receptor function or state of binding. The effects of an allosteric change on two probes may be very different; that is, the affinity of one probe (e.g., synthetic agonist) may decrease while the affinity of another (e.g., endogenous agonist) may increase or remain unaffected. There is no formalized order of effect on different ligands interacting with the receptor after allosteric change; thus, allosteric effects are not conserved across all bound orthosteric ligands. This is a major concern with regard to translating allosteric effects to a therapeutic setting. a situation wherein the rate of dissociation of a ligand from the receptor (e.g., agonist) is slow enough to block the binding of a competing ligand (e.g., antagonist). a pharmacological system has receptor reserve (or ‘spare receptors’) if a fraction of receptors can be irreversibly eliminated but still allow the agonist to produce a maximal response. High receptor reserves reflect high system sensitivity to the agonist such that partial agonists can appear ‘full’." @default.
• W2805372544 created "2018-06-13" @default.
• W2805372544 creator A5019867231 @default.
• W2805372544 creator A5062307345 @default.
• W2805372544 date "2018-08-01" @default.
• W2805372544 modified "2023-09-27" @default.
• W2805372544 title "PAM-Antagonists: A Better Way to Block Pathological Receptor Signaling?" @default.
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• W2805372544 doi "https://doi.org/10.1016/j.tips.2018.05.001" @default.
• W2805372544 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/29885909" @default.
• W2805372544 hasPublicationYear "2018" @default.
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