title: Further studies on the effect of lysine at the C-terminus of the Dmt-Tic opioid pharmacophore.
abstract: A wide range of activities are induced by Lys when introduced at C-terminus of the delta-opioid Dmt-Tic pharmacophore through the alpha-amine group, including: improved delta-antagonism, mu-agonism and mu-antagonism. Here we report the synthesis of a new series of compounds with the general formula H-Dmt-Tic-NH-(CH(2))(4)-CH(R)-R' (R=-NH(2), -NH-Ac, -NH-Z; R'=CO-NH-Ph, -CO-NH-CH(2)-Ph, -Bid) in which Lys is linked to Dmt-Tic through its side-chain amine group. All new compounds (1-9) displayed potent and selective delta-antagonism (MVD, pA(2)=7.81-8.27), which was independent of the functionalized alpha-amine and carboxylic groups of C-terminal Lys. This behaviour suggests a direct application as a prototype intermediate, such as Boc-Dmt-Tic-epsilon-Lys(Z)-OMe, which could be successfully applied in the synthesis (after Z or methyl ester removal) of unique designed multiple ligands containing the pharmacophore of the quintessential delta-antagonist Dmt-Tic and another opioid or biologically active non-opioid ligand.
authors.affiliation: Department of Toxicology, University of Cagliari, I-09124 Cagliari, Italy. gbalboni@unica.it <gbalboni@unica.it>
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Balboni
authors.forename: Valentina
authors.initials: V
authors.lastname: Onnis
authors.forename: Cenzo
authors.initials: C
authors.lastname: Congiu
authors.forename: Margherita
authors.initials: M
authors.lastname: Zotti
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ambo
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Bryant
authors.forename: Yunden
authors.initials: Y
authors.lastname: Jinsmaa
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Lazarus
authors.forename: Ilaria
authors.initials: I
authors.lastname: Lazzari
authors.forename: Claudio
authors.initials: C
authors.lastname: Trapella
authors.forename: Severo
authors.initials: S
authors.lastname: Salvadori
mesh_terms: D000818:Animals; D001665:Binding Sites; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006168:Guinea Pigs; D008024:Ligands; D008239:Lysine / Q000737:chemistry*; D008297:Male; D008968:Molecular Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C446951:2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; D004151:Dipeptides; D008024:Ligands; D011957:Receptors, Opioid; D044005:Tetrahydroisoquinolines; D008239:Lysine