TY - JOUR
T1 - A nontoxic pain killer designed by modeling of pathological receptor conformations
AU - Spahn, V.
AU - Del Vecchio, G.
AU - Labuz, D.
AU - Rodriguez-Gaztelumendi, A.
AU - Massaly, N.
AU - Temp, J.
AU - Durmaz, V.
AU - Sabri, P.
AU - Reidelbach, M.
AU - Machelska, H.
AU - Weber, M.
AU - Stein, C.
N1 - Funding Information:
This work was supported by Bundesministerium für Bildung und Forschung (VIP 0272/03V0364). We thank H. Schick and C. Wedler (ASCA GmbH) for continuous consulting, N. Vogel for technical assistance, M. Adjobo-Hermans for helpful advice and for donating the Venus-Gγ2 construct, O. Perepelica for initial computational simulations, P. Deuflhard and C. Zöllner for stimulating discussions, and B. Kieffer for critical comments on the manuscript. The Charité-Universitätsmedizin Berlin and the Zuse Institute Berlin have filed a patent on pH-dependent opioid receptor agonists (US 9133120 B2). A patent application on the computational methods (PCT/EP2013/102681) is pending. All data can be accessed at www.zib.de/ext-data/selective-opioids/.
Publisher Copyright:
© 2017, American Association for the Advancement of Science. All rights reserved.
PY - 2017/3/3
Y1 - 2017/3/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85014627129&partnerID=8YFLogxK
U2 - 10.1126/science.aai8636
DO - 10.1126/science.aai8636
M3 - Article
C2 - 28254944
AN - SCOPUS:85014627129
SN - 0036-8075
VL - 355
SP - 966
EP - 969
JO - Science
JF - Science
IS - 6328
ER -