Cyclic enkephalin analogues with exceptional potency and selectivity for delta-opioid receptors.
Superpotent and highly delta-opioid receptor selective cyclic peptides of the general formula H-Tyr-c[D-Pen-Gly-Phe(p-X)-Pen]-Phe-OH (where X = hydrogen or halogen) have been synthesized. In the binding assays the most selective and most potent compound is the p-bromophenyl-alanine-4 analogue (IC50 value = 0.19 nM, selectivity ratio = 21,000 for delta vs mu). In the GPI and MVD bioassays the most selective and most potent analogue is the p-fluoro-substituted analogue Tyr-[D-Pen-Gly-Phe(p-F)-Pen]-Phe-OH. In the MVD assay it has an exceptionally low IC50 value of 0.016 nM and a delta vs mu selectivity ratio of 45,000.
Hruby
V J
VJ
Department of Chemistry, University of Arizona, Tucson 85721, USA.
Bartosz-Bechowski
H
H
Davis
P
P
Slaninova
J
J
Zalewska
T
T
Stropova
D
D
Porreca
F
F
Yamamura
H I
HI
D000595:Amino Acid Sequence; D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D004745:Enkephalins / Q000138:chemical synthesis* / Q000494:pharmacology*; D006168:Guinea Pigs; D007700:Kinetics; D008297:Male; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000187:drug effects / Q000378:metabolism*; D013379:Substrate Specificity
D000700:Analgesics; D004745:Enkephalins; D010456:Peptides, Cyclic; D017465:Receptors, Opioid, delta