title: Structural studies of [2',6'-dimethyl-L-tyrosine1]endomorphin-2 analogues: enhanced activity and cis orientation of the Dmt-Pro amide bond.
abstract: 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.
authors.affiliation: Faculty of Pharmaceutical Sciences, Department of Medicinal Chemistry, Kobe Gakuin University, Nishi-ku, Kobe 651-2180, Japan. okada@pharm.kobegakuin.ac.jp
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Okada
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Fujita
authors.forename: Takashi
authors.initials: T
authors.lastname: Motoyama
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tsuda
authors.forename: Toshio
authors.initials: T
authors.lastname: Yokoi
authors.forename: Tingyou
authors.initials: T
authors.lastname: Li
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ambo
authors.forename: Yunden
authors.initials: Y
authors.lastname: Jinsmaa
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Bryant
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Lazarus
mesh_terms: 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
chemical_list: D000577:Amides; D009842:Oligopeptides; C105294:endomorphin 2