Conversion of the potent delta-opioid agonist H-Dmt-Tic-NH-CH(2)-bid into delta-opioid antagonists by N(1)-benzimidazole alkylation(1).
N(1)-Alkylation of 1H-benzimidizole of the delta agonist H-Dmt-Tic-NH-CH(2)-Bid with hydrophobic, aromatic, olefinic, acid, ethyl ester, or amide (1-6) became delta antagonists (pA(2)=8.52-10.14). delta- and micro-Opioid receptor affinities were high (K(i)delta=0.12-0.36 nM and K(i)micro=0.44-1.42 nM). Only delta antagonism (pA(2)=8.52-10.14) was observed; micro agonism (IC(50)=30-450 nM) was not correlated with changes in alkylating agent or delta antagonism, and some compounds yielded mixed delta antagonism/micro agonism.
Balboni
Gianfranco
G
Department of Toxicology, University of Cagliari, I-09124, Cagliari, Italy.
Guerrini
Remo
R
Salvadori
Severo
S
Negri
Lucia
L
Giannini
Elisa
E
Bryant
Sharon D
SD
Jinsmaa
Yunden
Y
Lazarus
Lawrence H
LH
D000478:Alkylation; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology; D004151:Dipeptides / Q000737:chemistry* / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013574:Synaptosomes / Q000187:drug effects; D014649:Vas Deferens / Q000187:drug effects
C507403:2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 1H-benzimidazol-2-ylmethylamide; D001562:Benzimidazoles; D004151:Dipeptides; D017465:Receptors, Opioid, delta; C031000:benzimidazole