ACS Medicinal Chemistry Letters
Letter
(6) Thompson, A. A.; Liu, W.; Chun, E.; Katritch, V.; Wu, H.; Vardy,
E.; Huang, X.-P.; Trapella, C.; Guerrini, R.; Calo, G.; Roth, B. L.;
Cherezov, V.; Stevens, R. C. Structure of the nociceptin/orphanin FQ
receptor in complex with a peptide mimetic. Nature 2012, 485, 395−
399.
(7) Manglik, A.; Kruse, A. C.; Kobilka, T. S.; Thian, F. S.; Mathiesen,
J. M.; Sunahara, R. K.; Pardo, L.; Weis, W. I.; Kobilka, B. K.; Granier,
S. Crystal structure of the μ-opioid receptor bound to a morphinan
antagonist. Nature 2012, 485, 321−326.
(8) Standard modeling techniques have been applied to dock,
optimize, and visualize the binding modes of our compounds as
implemented in MOE2012.10 (Molecular Operating Environment
2012, CCG, Montreal, Canada).
ASSOCIATED CONTENT
* Supporting Information
Assay description and experimental procedures for the
synthesis and characterization of selected compounds. This
material is available free of charge via the Internet at http://
■
S
AUTHOR INFORMATION
■
Corresponding Author
Notes
(9) Linz, K.; Christoph, T.; Tzschentke, T. M.; Koch, T.; Schiene, K.;
The authors declare no competing financial interest.
Gautrois, M.; Schroder, W.; Kogel, B. Y.; Beier, H.; Englberger, W.;
̈
̈
Schunk, S.; De Vry, J.; Jahnel, U.; Frosch, S. Cebranopadol: A novel
potent analgesic nociceptin/orphanin FQ peptide and opioid receptor
agonist. J. Pharmacol. Exp. Ther. 2014, 349, 535−548.
ACKNOWLEDGMENTS
■
We would like to thank H. Steinhagen, P. Ratcliffe, S. Frosch,
and E. Hoppe for very helpful discussions, F. Theil (ASCA
GmbH) for conception and realization of compounds, T. Koch
for obtaining NOP and MOP receptor binding data,and S.
(10) D’Amour, F. E.; Smith, D. L. A method for determining loss of
pain sensation. J. Pharmacol. Exp. Ther. 1941, 72, 74−79.
(11) Terlinden, R.; Kogel, B. Y.; Englberger, W.; Tzschentke, T.M. In
vitro and in vivo characterization of tapentadol metabolites. Methods
Find. Exp. Clin. Pharmacol. 2010, 32, 31−38.
Brenner, P. Gunther, B. Liebenhoff, M. Mulfarth, and R.
̈
̈
Woloszczak for technical assistance with the in vivo experi-
ments. Detailed 1H and NOE NMR analysis for determination
of stereochemical configuration by P. Jonas and M. Schade,
high-resolution mass by J. Bergstreiser and M. Fuhr, and
eADME characterization by S. Steufmehl are greatly acknowl-
edged.
(12) Hamill, O. P.; Marty, A.; Neher, E.; Sakmann, B.; Sigworth, F. J.
Improved patch-clamp techniques for high-resolution current record-
ing from cells and cell-free membrane patches. Pflugers Arch. 1981,
̈
391, 85−100.
(13) Zollner, C.; Stein, C. Opioids. Handb. Exp. Pharmacol. 2007,
̈
31−63.
(14) Dunham, N. W.; Miya, T. S. A note on a simple apparatus for
detecting neurological deficits in rats and mice. J. Am. Pharm. Assoc.
1957, 46, 208−209.
(15) Winter, L.; Nadeson, R.; Tucker, A. P.; Goodchild, C. S.
Antinociceptive properties of neurosteroids: A comparison of
alphadolone and alphaxalone in potentiation of opioid antinociception.
Anesth. Analg. 2003, 97, 798−805.
(16) Niemegeers, C. J. E.; Lenaerts, F. M.; Janssen, P. A. J.
Loperamide (R 18553), a novel type of antidiarrheal agent. Part 2: In
vivo parenteral pharmacology and acute toxicity in mice. Comparison
with morphine, codeine and diphenoxylate. Arzneimittelforschung 1974,
24, 1636−1641.
(17) Tzschentke, T. M.; de Vry, J.; Terlinden, R.; Hennies, H. H.;
Lange, C.; Strassburger, W.; Haurand, M.; Kolb, J.; Schneider, J.;
Buschmann, H.; Finkam, M.; Jahnel, U.; Friderichs, E. Tapentadol
hydrochloride. Analgesic, mu-opioid receptor agonist, noradrenaline
reuptake inhibitor. Drugs Future 2006, 31, 1053−1061.
(18) Meert, T. F.; Vermeirsch, H. A. A preclinical comparison
between different opioids: antinociceptive versus adverse effects.
Pharmacol., Biochem. Behav. 2005, 80, 309−326.
ABBREVIATIONS
■
CHO, Chinese hamster ovary cells; CI, confidence interval;
CNS, central nervous system; DOP, delta opioid peptide; EC50,
concentration with half-maximum inducible [35S]GTPγS bind-
ing; ED50, half-maximum effective dose; Emax, maximum
possible effect for the agonist; GTPγS, guanosine-5′-[γ-
thio]triphosphate; hNOPr, Human nociceptin/orphanin FQ
receptor; hMOPr, Human μ opioid receptor; HCl, hydro-
chloride; IC50, half-maximum inhibitory concentration; i.v.,
intravenous; Ki, dissociation constant for inhibitor binding;
KOP, kappa opioid peptide; MeCN, acetonitrile; MOP, mu
opioid peptide; MPE, maximum possible effect; NOEL, no
observed effect level; NOP, nociceptin/orphanin FQ peptide;
SNL, spinal nerve ligation; TES, triethylsilyl
REFERENCES
■
(1) Cremeans, C. M.; Gruley, E.; Kyle, D. J.; Ko, M.-C. Roles of μ-
opioid receptors and nociceptin/orphanin FQ peptide receptors in
buprenorphine-induced physiological responses in primates. J.
Pharmacol. Exp. Ther. 2012, 343, 72−81.
(2) Toll, L. The use of bifunctional NOP/Mu and NOP receptor
selective compounds for the treatment of pain, drug abuse, and
psychiatric disorders. Curr. Pharm. Des. 2013, 19, 7451−60.
(3) Schunk, S.; Linz, K.; Hinze, C.; Frormann, S.; Oberborsch, S.;
Sundermann, B.; Zemolka, S.; Englberger, W.; Germann, T.; Kless, A.;
̈
Christoph, T.; Kogel, B. Y.; Schroder, W.; Harlfinger, S.; Saunders, D.;
̈
̈
Sonnenschein, H. Discovery of spiro[cyclohexane-dihydropyrano[3,4-
b]indole]-amines as potent NOP and opioid receptor agonists. ACS
Med. Chem. Lett. 2014, DOI: 10.1021/ml500116x.
(4) Larock, R. C.; Yum, E. K. Synthesis of indoles via palladium-
catalyzed heteroannulation of internal alkynes. J. Am. Chem. Soc. 1991,
113, 6689−90.
(5) Hinze, C.; Aulenbacher, O.; Sundermann, B.; Oberboersch, S.;
Friderichs, E.; Englberger, W.; Koegel, B.-Y.; Linz, K.; Schick, H.;
Sonnenschein, H.; Henkel, B.; Rose, V. S.; Lipkin, M. J. Preparation of
spirocyclic indoles as ORL-1 receptor ligands for the treatment of pain.
U.S. Patent 8,053,576, Nov 8, 2011.
862
dx.doi.org/10.1021/ml500117c | ACS Med. Chem. Lett. 2014, 5, 857−862