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One Indole Ring to Rule Them All: How Modeling of Naltrindole Bound to the Delta Opioid Receptor Can Aid the Development of Novel Analgesics
Author(s) -
Arnold E.,
Bell N.,
Boesen T.,
Boldt N.,
Borden A.,
Bro J.,
Douglas M.,
Fuller J.,
Furumo Q.,
Gummin C.,
Keuler A.,
Kim D.,
Martinez A.,
Moldenhauer D.,
Mullooly I.,
NelsenFreund R.,
Ogunkunle D.,
Ortega L.,
Palmersheim S.,
Sabatino T.,
Schwabe B.,
Sung R.,
Trzcinski K.,
Ulschmid C.,
Klestinski K.,
Kaiser C.,
Vogt D.,
Cunningham C. W.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.lb171
Subject(s) - naltrindole , oxycodone , analgesic , morphine , pharmacology , δ opioid receptor , chemistry , opioid , antagonist , chronic pain , opioid receptor , medicine , receptor , biochemistry , physical therapy
According to the Institute of Medicine, 116 million Americans suffer from chronic pain, costing over $500 billion annually. As such, the use of pain‐killing drugs like morphine and oxycodone has increased dramatically over the past decade. Analgesic effects are produced through agonism, or activation, of the body's mu (MOR) and delta (DOR) opioid receptors, which are G‐coupled protein receptors. Tolerance, the decreased analgesic effect of MOR agonists after prolonged use, is a major problem facing opioid pain management. A drug that antagonizes, or inhibits, DOR can greatly reduce the development of tolerance to MOR agonists, offering new pain therapy potentials. One example of a selective DOR antagonist is naltrindole (NTI), which has a similar structure as morphine, except for a cyclopropylmethyl group on its nitrogen substituent and a bulky indole group. The large indole ring negatively interacts with the W318 residue on MOR but is able to bond with W284 residue on the DOR, producing DOR‐selective antagonism. Co‐administration of NTI with morphine represents a potential new approach to producing analgesics with less tolerance. Understanding the structure of this ligand and enzyme may further structure‐based drug designs. The Marquette University High School SMART Team (Students Modeling A Research Topic) modeled naltrindole bound to DOR using 3‐D printing technology. Supported by a grant from the NIH‐CTSA.