Conversion of the potent delta-opioid agonist H-Dmt-Tic-NH-CH(2)-bid into delta-opioid antagonists by N(1)-benzimidazole alkylation(1)

J Med Chem. 2005 Dec 29;48(26):8112-4. doi: 10.1021/jm058259l.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylation
  • Animals
  • Benzimidazoles / chemistry*
  • Benzimidazoles / pharmacology
  • Dipeptides / chemistry*
  • Dipeptides / pharmacology
  • Guinea Pigs
  • Ileum / drug effects
  • Inhibitory Concentration 50
  • Male
  • Mice
  • Rats
  • Receptors, Opioid, delta / agonists*
  • Receptors, Opioid, delta / antagonists & inhibitors*
  • Synaptosomes / drug effects
  • Vas Deferens / drug effects

Substances

  • 2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 1H-benzimidazol-2-ylmethylamide
  • Benzimidazoles
  • Dipeptides
  • Receptors, Opioid, delta
  • benzimidazole