Title:A Common Molecular Motif Characterizes Extracellular Allosteric Enhancers of GPCR Aminergic Receptors and Suggests Enhancer Mechanism of Action
Volume: 21
Issue: 32
Author(s): Robert Root-Bernstein and Patrick F. Dillon
Affiliation:
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.
Abstract: 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.
