Synthesis and structure-activity relationships of [MeTyr1, MeArg7]-dynorphin A(1-8)-OH analogues with substitution at position 8.
A series of [MeTyr1, MeArg7]-Dynorphin A (Dyn)(1-8)-OH analogues, modified at position 8 with various amino acids, is described. Their biological activities were determined in the three bioassays [guinea pig ileum (GPI), mouse vas deferens (MVD), and rabbit vas deferens (RVD)] and in the mouse tail-pinch test after subcutaneous administration. None of the analogues tested displayed more potent kappa-opioid activity in the RVD than [MeTyr1, MeArg7, D-Leu8]-Dyn(1-8)-NHEt (1), which is a potent analgesic peptide with similar opioid receptor selectivity to that of Dyn. However, [MeTyr1, MeArg7, Melle8]-Dyn(1-8)-OH (11) showed about a twofold more potent analgesic effect than 1. Based on the obtained results it is conceivable that in the case of Dyn(1-8)-OH analogues both a lipophilic L-amino acid in position 8 and an unchanged 7-8 amide bond are essential to maintain potent kappa-opioid activity.
Yoshino
H
H
Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
Kaneko
T
T
Arakawa
Y
Y
Nakazawa
T
T
Yamatsu
K
K
Tachibana
S
S
D000818:Animals; D004399:Dynorphins / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D013329:Structure-Activity Relationship
D010446:Peptide Fragments; D004399:Dynorphins; C026770:dynorphin (1-8)