title: Development of potent mu-opioid receptor ligands using unique tyrosine analogues of endomorphin-2.
abstract: Six analogues of tyrosine, which contained alkyl groups at positions 2', 3', and 6', either singly or in combination on the tyramine ring, were investigated for their effect on the opioid activity of [Xaa(1)]endomorphin-2 (EM-2). The opioid analogues displayed the following characteristics: (i) high mu-opioid receptor affinity [K(i)(mu) = 0.063-2.29 nM] with selectivity [K(i)(delta)/K(i)(mu)] ranging from 46 to 5347; (ii) potent functional mu-opioid agonism [GPI assay (IC(50) = 0.623-0.924 nM)] and with a correlation between delta-opioid receptor affinities and functional bioactivity using MVD; (iii) intracerebroventricular administration of [Dmt(1)]- (14) and [Det(1)]EM-2 (10) produced a dose-response antinociception in mice, with the former analogue more active than the latter; and (iv) a marked shift occurred from the trans-orientation at the Tyr(1)-Pro(2) bond to a cis-conformer compared to that observed previously with [Dmt(1)]EM-2 (14) (Okada et al. Bioorg. Med. Chem. 2003, 11, 1983-1984) except [Mmt(1)]EM-2 (7). The active profile of the [Xaa(1)]EM-2 analogues indicated that significant modifications on the tyramine ring are possible while high biological activity is maintained.
authors.affiliation: The Graduate School of Food and Medicinal Sciences, Faculty of Pharmaceutical Sciences, and High Technology Research Center, Kobe Gakuin University, Nishi-ku, Kobe 651-2180, Japan.
authors.forename: Tingyou
authors.initials: T
authors.lastname: Li
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Fujita
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tsuda
authors.forename: Anna
authors.initials: A
authors.lastname: Miyazaki
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ambo
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sasaki
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
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Okada
mesh_terms: D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
chemical_list: D000701:Analgesics, Opioid; D008024:Ligands; D009842:Oligopeptides; D017450:Receptors, Opioid, mu; C105294:endomorphin 2; D014443:Tyrosine