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Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

A Common Molecular Motif Characterizes Extracellular Allosteric Enhancers of GPCR Aminergic Receptors and Suggests Enhancer Mechanism of Action

Author(s): Robert Root-Bernstein and Patrick F. Dillon

Volume 21, Issue 32, 2014

Page: [3673 - 3686] Pages: 14

DOI: 10.2174/0929867321666140826120604


Several classes of compounds that have no intrinsic activity on aminergic systems nonetheless enhance the potency of aminergic receptor ligands three-fold or more while significantly increasing their duration of activity, preventing tachyphylaxis and reversing fade. Enhancer compounds include ascorbic acid, ethylenediaminetetraacetic acid, corticosteroids, opioid peptides, opiates and opiate antagonists. This paper provides the first review of aminergic enhancement, demonstrating that all enhancers have a common, inobvious molecular motif and work through a common mechanism that is manifested by three common characteristics. First, aminergic enhancers bind directly to the amines they enhance, suggesting that the common structural motif is reflected in common binding targets. Second, one common target is the first extracellular loop of aminergic receptors. Third, at least some enhancers are antiphosphodiesterases. These observations suggest that aminergic enhancers act on the extracellular surface of aminergic receptors to keep the receptor in its high affinity state, trapping the ligand inside the receptor. Enhancer binding produces allosteric modifications of the receptor structure that interfere with phosphorylation of the receptor, thereby inhibiting down-regulation of the receptor. The mechanism explains how enhancers potentiate aminergic activity and increase duration of activity and makes testable predictions about additional compounds that should act as aminergic enhancers.

Keywords: aldosterone, allosteric, allostery, antiphosphodiesterase, ascorbic acid, corticosteroid, dopamine, down-regulation, EDTA, enhancement, enhances, epinephrine, GPCR, histamine, increased potency, molecular complementarity, morphine, naloxone, naltrexone, norepinephrine, opiate, opioid, phosphodiesterase inhibitors, potentiates, potentiation, serotonin, supersensitivity, vitamin C.

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