Synthesis and receptor binding of Cys-endomorphin

This paper describes the synthesis and binding profile of a new analog of e ndomorphin, Cys-endomorphin (C-Y-P-W-F-NH2), to mu- and delta-opioid recept ors in rat brain. The new derivative displayed an IC50 of 16+/-4.7 and >10, 000 nM against the mu-selective [H-3] endomorphin-2 and the highly delta-s pecific [H-3]Ile(5,6)-deltorphin II, respectively. Thus, Cysendomorphin als o favors mu- versus delta-opioid binding sites similarly to the parent pept ide. The new ligand displayed weak potency with an IC50 of 3,800 nM for [H- 3] naloxone binding. Even in 10(-5) M, the highest concentration tested, Cy s-endomorphin was not able to produce 50% inhibition of [H-3]naloxone bindi ng in the presence of 100 mM Na+. The data, however, indicated that the ago nistic character of endomorphins was retained for the new analog. The diffe rence in the affinity of Cys-endomorphin for peptides versus naloxone suppo rts previous observations with other mu-opioid ligands, namely that distinc t domains of the receptor might participate in the binding of these structu rally different compounds.