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.