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A nontoxic pain killer designed by modeling of pathological receptor conformations
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Journal Article
A nontoxic pain killer designed by modeling of pathological receptor conformations
2017
Overview
Indiscriminate activation of opioid receptors provides pain relief but also severe central and intestinal side effects. We hypothesized that exploiting pathological (rather than physiological) conformation dynamics of opioid receptor-ligand interactions might yield ligands without adverse actions. By computer simulations at low pH, a hallmark of injured tissue, we designed an agonist that, because of its low acid dissociation constant, selectively activates peripheral μ-opioid receptors at the source of pain generation. Unlike the conventional opioid fentanyl, this agonist showed pH-sensitive binding, heterotrimeric guanine nucleotide–binding protein (G protein) subunit dissociation by fluorescence resonance energy transfer, and adenosine 3′,5′-monophosphate inhibition in vitro. It produced injury-restricted analgesia in rats with different types of inflammatory pain without exhibiting respiratory depression, sedation, constipation, or addiction potential.
Publisher
American Association for the Advancement of Science,The American Association for the Advancement of Science
Subject
/ Adenosine Monophosphate - antagonists & inhibitors
/ Analgesics, Opioid - adverse effects
/ Analgesics, Opioid - chemistry
/ Analgesics, Opioid - pharmacology
/ Animals
/ Constipation - chemically induced
/ Fentanyl
/ Fentanyl - analogs & derivatives
/ Fluorescence Resonance Energy Transfer
/ GTP-Binding Protein alpha Subunits - metabolism
/ Guanine
/ Guanine nucleotide-binding protein
/ Humans
/ Injuries
/ Ligands
/ Pain
/ Piperidines - adverse effects
/ Proteins
/ Rats
/ Receptors, Opioid, mu - agonists
/ Receptors, Opioid, mu - chemistry
/ Receptors, Opioid, mu - genetics
/ Respiratory Insufficiency - chemically induced
/ Trauma
