ACS Medicinal Chemistry Letters
Letter
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(14) 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).
(15) For 2D interaction plot, see Supporting Information.
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AUTHOR INFORMATION
Corresponding Author
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We 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, J. Glembin
for carrying out the electrophysiology in the papillary muscle
model, and S. Brenner, P. Gunther, B. Liebenhoff, M. Mulfarth,
̈
̈
H .J. Weber, and R. Woloszczak for technical assistance with
the in vivo experiments. Detailed 2D NMR analysis for
determination of stereochemical configuration by O. Aulen-
bacher, P. Jonas, and M. Schade, high-resolution mass by J.
Bergstreiser and M. Fuhr, and eADME characterization by S.
Steufmehl are greatly acknowledged.
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 peptide receptor; HCl,
hydrochloride; IC50, half-maximum inhibitory concentration;
i.v., intravenous; Ki, dissociation constant for inhibitor binding;
KOP, kappa opioid peptide; MOP, mu opioid peptide; MPE,
maximum possible effect; NOP, nociceptin/orphanin FQ
peptide; r, receptor; SNL, spinal nerve ligation
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dx.doi.org/10.1021/ml500116x | ACS Med. Chem. Lett. 2014, 5, 851−856