Agonist and antagonist profiles of [D-Ala2,Glu4]deltorphin and its [Cys4]- and [Ser4]-substituted derivatives: further evidence of opioid delta receptor multiplicity

PJ Horan, KD Wild, A Misicka, A Lipkowski, RC Haaseth, VJ Hruby, SJ Weber, TP Davis, HI Yamamura and F Porreca

Department of Pharmacology, University of Arizona, Tucson.

Pharmacological evidence has suggested the presence of two supraspinal opioid delta receptor subtypes in the mouse, termed delta-1 and delta- 2. [D-Pen2,D-Pen5]enkephalin (DPDPE) is thought to be primarily an agonist at the opioid delta-1 subtype, whereas H2N-Tyr-D-Ala-Phe-Glu- Val-Val-Gly-NH2 ([D-Ala2,Glu4]deltorphin) is a selective agonist at the delta-2 subtype. Based on previous reports suggesting that a receptor sulfhydryl group may be critical for ligand binding to the opioid delta receptor, the present investigation has attempted to discover whether this concept extends to the opioid delta-2 receptor. For this purpose, a cysteine-substituted deltorphin was synthesized and the potential agonist and antagonist properties of this compound, H2N-Tyr-D-Ala-Phe- Cys-Val-Val-Gly-NH2 ([D-Ala2,Cys4]deltorphin), were evaluated in an antinociceptive assay after i.c.v. administration to mice and stability in mouse brain was determined. As a control a serine-substituted deltorphin was also prepared and the potential agonist and antagonist properties of this compound, H2N-Tyr-D-Ala-Phe-Ser-Val-Val-Gly-NH2 ([D- Ala2,Ser4]deltorphin), as well as those of the parent deltorphin, [D- Ala2,Glu4]deltorphin, were evaluated. Acutely, [D-Ala2,Cys4]deltorphin, [D-Ala2,Ser4]deltorphin and [D-Ala2,Glu4]deltorphin each produced dose- related antinociceptive effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 265, Issue 2, pp. 896-902, 05/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				A. Kalra, M. O. Urban, and K. A. Sluka Blockade of Opioid Receptors in Rostral Ventral Medulla Prevents Antihyperalgesia Produced by Transcutaneous Electrical Nerve Stimulation (TENS) J. Pharmacol. Exp. Ther., July 1, 2001; 298(1): 257 - 263. [Abstract] [Full Text]

				E. J. Bilsky, X. Qian, V. J. Hruby, and F. Porreca Antinociceptive Activity of [beta -Methyl-2',6'-dimethyltyrosine1]-Substituted Cyclic [D-Pen2,D-Pen5]Enkephalin and [D-Ala2,Asp4]Deltorphin Analogs J. Pharmacol. Exp. Ther., April 1, 2000; 293(1): 151 - 158. [Abstract] [Full Text]

				S. A. Thomas, T. J. Abbruscato, V. S. Hau, T. J. Gillespie, J. Zsigo, V. J. Hruby, and T. P. Davis Structure-Activity Relationships of a Series of [D-Ala2]Deltorphin I and II Analogues; in Vitro Blood-Brain Barrier Permeability and Stability J. Pharmacol. Exp. Ther., May 1, 1997; 281(2): 817 - 825. [Abstract] [Full Text]