Author/Authors :
Yoshio Okada، نويسنده , , Yoshio Fujita، نويسنده , , Takashi Motoyama، نويسنده , , Yuko Tsuda، نويسنده , , Toshio Yokoi، نويسنده , , Tingyou Li، نويسنده , , Yusuke Sasaki، نويسنده , , Akihiro Ambo، نويسنده , , Yunden Jinsmaa، نويسنده , , Sharon D. Bryant، نويسنده , , Lawrence H. Lazarus، نويسنده ,
Abstract :
Analogues of endomorphin-2 (EM-2: Tyr-Pro-Phe-Phe-NH2) (1) were designed to examine the importance of each residue on μ-opioid receptor interaction. Replacement of Tyr1 by 2′,6′-dimethyl-l-tyrosine (Dmt) (9–12) exerted profound effects: [Dmt1]EM-2 (9) elevated μ-opioid affinity 4.6-fold (Kiμ=0.15 nM) yet selectivity fell 330-fold as δ-affinity rose (Kiδ=28.2 nM). This simultaneous increased μ- and δ-receptor bioactivities resulted in dual agonism (IC50=0.07 and 1.87 nM, respectively). While substitution of Phe4 by a phenethyl group (4) decreased μ affinity (Kiμ=13.3 nM), the same derivative containing Dmt (12) was comparable to EM-2 but also acquired weak δ antagonism (pA2=7.05). 1H NMR spectroscopy revealed a trans configuration (1:2 to 1:3, cis/trans) in the Tyr-Pro amide bond, but a cis configuration (5:3 to 13:7, cis/trans) with Dmt-Pro analogues.
