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Discovery of a Novel Selective Kappa-Opioid Receptor Agonist Using Crystal Structure-Based Virtual Screening

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Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
‡ § Departments of Psychiatry and §Pharmacology, Columbia University, College of Physicians and Surgeons, New York, New York 10032, United States
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045, United States
Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York, 10032, United States
*Mailing Address: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1677, New York, NY 10029. Tel.: 212-659-8690. Fax: 212-849-2456. E-mail: [email protected]
Cite this: J. Chem. Inf. Model. 2013, 53, 3, 521–526
Publication Date (Web):March 5, 2013
Copyright © 2013 American Chemical Society

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    Kappa-opioid (KOP) receptor agonists exhibit analgesic effects without activating reward pathways. In the search for nonaddictive opioid therapeutics and novel chemical tools to study physiological functions regulated by the KOP receptor, we screened in silico its recently released inactive crystal structure. A selective novel KOP receptor agonist emerged as a notable result and is proposed as a new chemotype for the study of the KOP receptor in the etiology of drug addiction, depression, and/or pain.

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    General procedures for the synthesis of MCKK-17S and MCKK-17R. Table S1: List of the 22 tested compounds. Table S2: Details of the 500 top-scoring docked compounds from virtual screening at the KOP receptor. Figure S1: Plot of competitive inhibition of 3H-diprenorphine binding at the KOP receptor. Figure S2 Synthetic scheme used to obtain MCKK-17R and MCKK-17S stereoisomers. Figure S3 shows the cAMP accumulation inhibition curves at DOP and MOP receptors. This information is available free of charge via the Internet at

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