Portal de Periódicos da CAPES

Stereochemical Requirements for Receptor Recognition of the μ-Opioid Peptide Endomorphin-1

2000; Elsevier BV; Volume: 78; Issue: 2 Linguagem: Inglês

10.1016/s0006-3495(00)76619-7

1542-0086

Marta Paterlini, Francesca Avitabile, Beverly Gaul Ostrowski, David M. Ferguson, Philip S. Portoghese,

Receptor Mechanisms and Signaling

A series of diastereoisomers of endomorphin-1 (EM1, Tyr1-Pro2-Trp3-Phe4-NH2) have been synthesized and their potency measured using the guinea pig ileum assay. [d-Phe4]EM1 possessed 1/10 the potency of EM1, while potencies of [d-Tyr1]EM1 and [d-Trp3]EM1 were 50- and 100-fold lower, respectively. Drastic loss of activity occurred in the [d-Pro2]EM1 peptide. The structural determinants for the inactivity and reduced potency of the diastereoisomers were investigated using NMR spectroscopy and conformational analysis. Simulations of trans-[d-Pro2]EM1 using NOE-derived distance constraints afforded well-defined structures in which Tyr and Trp side chains stack against the proline ring. The inactivity of [d-Pro2]EM1 was explained by structural comparison with EM1 (Podlogar et al.,1998, FEBS Lett. 439:13–20). The two peptides showed an opposite orientation of the Trp3 residue with respect to Tyr1, thus suggesting a role of Pro2 as a stereochemical spacer in orienting Trp3 and Phe4 toward regions suitable for μ-receptor interaction. The agonist activity of [d-Tyr1]EM1 and [d-Trp3]EM1 was attributed to their ability to adopt low-energy conformations that mimic those of EM1. The requirements for μ-receptor activation were examined further by comparing EM1 with the μ-peptide [d-Ala2, MePhe4, Gly-ol]-enkephalin (DAMGO). Conformations of DAMGO with a Tyr1-MePhe4 phenyl ring separation of ∼12 Å were found to mimic Tyr1-Phe4 of EM1, thus suggesting overlapping binding modes between these two peptides.