Dermorphin analogues containing D-kyotorphin: structure-antinociceptive relationships in mice.
The antinociceptive effects of synthetic dermorphin and its analogues containing D-Arg in position 2 injected into the lateral cerebroventricle were examined in conscious mice. Intracerebroventricular (i.c.v.) administration of dermorphin and [D-Arg2] dermorphin produced potent and long-lasting antinociceptive activity as assayed by the tail-pressure test. Dermorphin and [D-Arg2] dermorphin were 210 and 52 times more potent than morphine, respectively. The antinociceptive effects produced by these heptapeptides were antagonized by a low dose (0.5 mg kg-1, i.p.) of the opioid antagonist naloxone. The ED50 values for [D-Arg2] dermorphin (1-6), (1-5) and (1-4) were not significantly different from that for [D-Arg2] dermorphin. The potency of the shortest fragment, [D-Arg2] dermorphin (1-2) was found to possess a severely reduced activity, whilst [D-Arg2] dermorphin (1-3) maintained activity and was 10 times more potent than morphine. [D-Arg2] dermorphin analogues showed almost identical effects when tested on the electrically-induced contractions of the guinea-pig isolated ileum. These results led us to conclude that the presence of the N-terminal tripeptide in the structure of [D-Arg2] dermorphin is of crucial importance for the manifestation of the full intrinsic opioid-like antinociceptive activity of [D-Arg2] dermorphin, which is presumably mediated through opioid receptors in the brain.
Kisara
K
K
Sakurada
S
S
Sakurada
T
T
Sasaki
Y
Y
Sato
T
T
Suzuki
K
K
Watanabe
H
H
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology*; D018847:Opioid Peptides; D010446:Peptide Fragments / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000701:Analgesics, Opioid; D009842:Oligopeptides; D018847:Opioid Peptides; D010446:Peptide Fragments; C030058:dermorphin; C045484:dermorphin, Arg(2)-