title: A nontoxic pain killer designed by modeling of pathological receptor conformations.
abstract: 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.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Charité-Universitätsmedizin Berlin Campus Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, Berlin 12203, Germany.
authors.forename: V
authors.identifier: 0000-0002-8086-8090
authors.initials: V
authors.lastname: Spahn
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Charité-Universitätsmedizin Berlin Campus Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, Berlin 12203, Germany.
authors.forename: G
authors.identifier: 0000-0002-2726-2014
authors.initials: G
authors.lastname: Del Vecchio
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Charité-Universitätsmedizin Berlin Campus Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, Berlin 12203, Germany.
authors.forename: D
authors.identifier: 0000-0003-2465-4730
authors.initials: D
authors.lastname: Labuz
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Charité-Universitätsmedizin Berlin Campus Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, Berlin 12203, Germany.
authors.forename: A
authors.identifier: 0000-0002-5402-2788
authors.initials: A
authors.lastname: Rodriguez-Gaztelumendi
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Charité-Universitätsmedizin Berlin Campus Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, Berlin 12203, Germany.
authors.forename: N
authors.identifier: 0000-0003-3440-5957
authors.initials: N
authors.lastname: Massaly
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Charité-Universitätsmedizin Berlin Campus Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, Berlin 12203, Germany.
authors.forename: J
authors.identifier: 0000-0003-2523-798X
authors.initials: J
authors.lastname: Temp
authors.affiliation: Computational Molecular Design, Zuse-Institut Berlin, Takustrasse 7, Berlin, 14195, Germany.
authors.forename: V
authors.identifier: 0000-0002-1633-4190
authors.initials: V
authors.lastname: Durmaz
authors.affiliation: Computational Molecular Design, Zuse-Institut Berlin, Takustrasse 7, Berlin, 14195, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Sabri
authors.affiliation: Computational Molecular Design, Zuse-Institut Berlin, Takustrasse 7, Berlin, 14195, Germany.
authors.forename: M
authors.identifier: 0000-0002-1919-1834
authors.initials: M
authors.lastname: Reidelbach
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Charité-Universitätsmedizin Berlin Campus Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, Berlin 12203, Germany.
authors.forename: H
authors.identifier: 0000-0001-6315-2958
authors.initials: H
authors.lastname: Machelska
authors.affiliation: Computational Molecular Design, Zuse-Institut Berlin, Takustrasse 7, Berlin, 14195, Germany.
authors.forename: M
authors.identifier: 0000-0003-3939-410X
authors.initials: M
authors.lastname: Weber
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Charité-Universitätsmedizin Berlin Campus Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, Berlin 12203, Germany. christoph.stein@charite.de.
authors.forename: C
authors.identifier: 0000-0001-5240-6836
authors.initials: C
authors.lastname: Stein
mesh_terms: D059787:Acute Pain / Q000188:drug therapy*; D000249:Adenosine Monophosphate / Q000037:antagonists & inhibitors; D000698:Analgesia; D000701:Analgesics, Opioid / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D003198:Computer Simulation; D003248:Constipation / Q000139:chemically induced; D015195:Drug Design; D005283:Fentanyl / Q000009:adverse effects / Q000031:analogs & derivatives*; D031541:Fluorescence Resonance Energy Transfer; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D008958:Models, Molecular; D059408:Pain Management; D010880:Piperidines / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000737:chemistry* / Q000235:genetics; D012131:Respiratory Insufficiency / Q000139:chemically induced; D014162:Transfection
chemical_list: D000701:Analgesics, Opioid; D044385:GTP-Binding Protein alpha Subunits; D008024:Ligands; C000624316:N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenylpropionamide; D010880:Piperidines; D017450:Receptors, Opioid, mu; D000249:Adenosine Monophosphate; D005283:Fentanyl