Structural studies of [2',6'-dimethyl-L-tyrosine1]endomorphin-2 analogues: enhanced activity and cis orientation of the Dmt-Pro amide bond.
Analogues of endomorphin-2 (EM-2: Tyr-Pro-Phe-Phe-NH(2)) (1) were designed to examine the importance of each residue on mu-opioid receptor interaction. Replacement of Tyr(1) by 2',6'-dimethyl-L-tyrosine (Dmt) (9-12) exerted profound effects: [Dmt(1)]EM-2 (9) elevated mu-opioid affinity 4.6-fold (K(i mu=0.15 nM) yet selectivity fell 330-fold as delta-affinity rose (K(i)delta=28.2 nM). This simultaneous increased mu- and delta-receptor bioactivities resulted in dual agonism (IC(50)=0.07 and 1.87 nM, respectively). While substitution of Phe(4) by a phenethyl group (4) decreased mu affinity (K(i)mu=13.3 nM), the same derivative containing Dmt (12) was comparable to EM-2 but also acquired weak delta antagonism (pA(2)=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.
Okada
Yoshio
Y
Faculty of Pharmaceutical Sciences, Department of Medicinal Chemistry, Kobe Gakuin University, Nishi-ku, Kobe 651-2180, Japan. okada@pharm.kobegakuin.ac.jp
Fujita
Yoshio
Y
Motoyama
Takashi
T
Tsuda
Yuko
Y
Yokoi
Toshio
T
Li
Tingyou
T
Sasaki
Yusuke
Y
Ambo
Akihiro
A
Jinsmaa
Yunden
Y
Bryant
Sharon D
SD
Lazarus
Lawrence H
LH
D000577:Amides / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D008968:Molecular Conformation; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
D000577:Amides; D009842:Oligopeptides; C105294:endomorphin 2