AGONIST AND ANTAGONIST PROFILES OF [D-ALA(2), GLU(4)] DELTORPHIN AND ITS [CYS(4)]-SUBSTITUTED AND [SER(4)]-SUBSTITUTED DERIVATIVES - FURTHER EVIDENCE OF OPIOID DELTA-RECEPTOR MULTIPLICITY

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 a gonist at the opioid delta-1 subtype, whereas H2N-Tyr-D-Ala-Phe-Glu-Va l-Val-Gly-NH2 ([D-Ala2, Glu4] deltorphin) is a selective agonist at th e delta-2 subtype. Based on previous reports suggesting that a recepto r sulfhydryl group may be critical for ligand binding to the opioid de lta receptor, the present investigation has attempted to discover whet her this concept extends to the opioid delta-2 receptor. For this purp ose, a cysteine-substituted deltorphin was synthesized and the potenti al agonist and antagonist properties of this compound, H2N-Tyr-D-Ala-P he-Cys-Val-Val-Gly-NH2 ([D-Ala2, CyS4]deltorphin), were evaluated in a n antinociceptive assay after i.c.v. administration to mice and stabil ity 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, Ser]deltorphin), as well as those of the parent deltorphin, [D- Ala2, Glu4] deltorphin, were evaluated. Acutely, [D-Ala2, CyS4]deltorp hin, [D-Ala2, Ser]deltorphin and [D-Ala2, Glu4]deltorphin each produce d dose-related antinociceptive effects. Pretreatment with a single i.c .v. injection Of [D-Ala2, CyS4]deltorphin, [D-Ala2, Ser4]deltorphin or [D-Ala2, Glu4]deltorphin blocked the antinociceptive effects of [D-Al a2, Glu4]deltorphin (delta-2 agonist) for up to 24 hr, but not the ant inociceptive effects of DPDPE (delta-1 agonist). Pretreatment with a s ingle dose [D-Ser2, Leu5, Thr6]enkephalin (DSLET) (delta-2 agonist) fa iled to affect [D-Ala2, Glu4]deltorphin-mediated antinociception, sugg esting that the antagonistic actions of the deltorphin derivatives wer e not due to the production of acute tolerance. From these data, we po stulate that an intact thiol group is apparently not critical for the binding of these ligands at the opioid delta-2 receptor.