A novel cyclic opioid peptide analog showing high preference for mu-receptors.
The side-chain to side-chain cyclized opioid peptide analogs H-Tyr-D-Orn-Phe-Asp-NH2 (I) and H-Tyr-D-Lys-Phe-Glu-NH2 (II) were synthesized and tested in the guinea pig ileum and mouse vas deferens assays and in binding assays based on displacement of mu- and delta-opioid receptor-selective radioligands from rat brain membranes. The more rigid cyclic analog I containing a 13-membered ring structure showed very high preference for mu-receptors over delta-receptors, whereas the more flexible cyclic peptide II (15-membered ring) was non-selective. These results indicate that variation in the degree of conformational restriction of opioid peptides can produce drastic shifts in their receptor selectivity profile. Because of its high mu-receptor selectivity and rigidity cyclic analog I will be useful for determining the conformational requirements of mu-opioid receptors.
Schiller
P W
PW
Nguyen
T M
TM
Maziak
L
L
Lemieux
C
C
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D004723:Endorphins / Q000138:chemical synthesis* / Q000378:metabolism; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000378:metabolism; D011487:Protein Conformation; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism*; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D013329:Structure-Activity Relationship; D013552:Swine; D014649:Vas Deferens / Q000187:drug effects
D004723:Endorphins; D010456:Peptides, Cyclic; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu