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NEUROPHARMACOLOGY

Systemic and Spinal Analgesic Activity of a -Opioid-Selective Lanthionine Enkephalin Analog

Department of Anesthesiology, University of California, San Diego, La Jolla, California (C.I.S., S.M., T.L.Y.); Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California (Y.R., J.P.T., M.G.); and Clinical Research Institute of Montreal, Montreal, Quebec, Canada (P.W.S.)

A lanthionine enkephalin derivative, Tyr-c[D-Val_L-Gly-Phe-D-Ala_L]-OH (DV_L²DA_L⁵LanEnk), where Val_L and Ala_L denote the lanthionine amino acid ends linked via a monosulfide bridge to form the lanthionine structure, was synthesized. It was found to possess selectivity for and potency at the versus µ opioid receptor as defined by binding studies and by its respective activity on the mouse vas deferens compared with the guinea pig ileum. The agent produced a potent analgesia after intrathecal and intraperitoneal delivery with ED₅₀ values being, respectively, 0.19 µg and 0.49 mg/kg. The effects of the agent were reversed by the -selective antagonist naltrindole. These analgesic actions occurred at doses that had no effect upon general behavior or motor function. These results suggest a potent -preferring agent suitable for development as a systemic opioid analgesic.

Address correspondence to: Dr. Tony L. Yaksh, Department of Anesthesiology, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0818. E-mail: tyaksh{at}ucsd.edu

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