Further studies on the effect of lysine at the C-terminus of the Dmt-Tic opioid pharmacophore.
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.
Balboni
Gianfranco
G
Department of Toxicology, University of Cagliari, I-09124 Cagliari, Italy. gbalboni@unica.it <gbalboni@unica.it>
Onnis
Valentina
V
Congiu
Cenzo
C
Zotti
Margherita
M
Sasaki
Yusuke
Y
Ambo
Akihiro
A
Bryant
Sharon D
SD
Jinsmaa
Yunden
Y
Lazarus
Lawrence H
LH
Lazzari
Ilaria
I
Trapella
Claudio
C
Salvadori
Severo
S
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*
C446951:2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; D004151:Dipeptides; D008024:Ligands; D011957:Receptors, Opioid; D044005:Tetrahydroisoquinolines; D008239:Lysine