Agonist and antagonist profiles of [D-Ala2,Glu4]deltorphin and its [Cys4]- and [Ser4]-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 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)
Department of Pharmacology, University of Arizona, Tucson.
P J
PJ
Horan
K D
KD
Wild
A
A
Misicka
A
A
Lipkowski
R C
RC
Haaseth
V J
VJ
Hruby
S J
SJ
Weber
T P
TP
Davis
H I
HI
Yamamura
F
F
Porreca
D000595:Amino Acid Sequence; D000700:Analgesics / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001923:Brain Chemistry; D003545:Cysteine / Q000737:chemistry; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors / Q000145:classification / Q000187:drug effects*; D012694:Serine / Q000737:chemistry
D000700:Analgesics; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; C060209:deltorphin II, Ala(2)-; D012694:Serine; D004743:Enkephalin, Leucine; C034318:enkephalin, Ser(2), Leu(5), Thr(6)-; D003545:Cysteine