Synthesis and opioid activity of N,N-dimethyl-Dmt-Tic-NH-CH(R)-R ' analogues: Acquisition of potent delta antagonism

N,N-Dimethylation of the H-Dmt-Tic-NH-CH(R)-R0 series of compounds produced no significant affect on the high d-opioid receptor affinity (Ki=0.035–0.454 nM), but dramatically decreased that for the m-opioid receptor. The effect of N-methylation was independent of the length of the linker (R); however, the bioactivities were affected by the chemical composition of the third aromatic group (R0): phenyl (Ph) (50–80) elicited a greater reduction in m-affinity (40–70-fold) compared to analogues containing 1H-benzimidazole-2-yl (Bid) (9-fold). The major consequences of N,N-dimethylation on in vitro bioactivity were: (i) a loss of d-agonism coupled with the appearance of potent d antagonism (40–70) (pA2=8.14–9.47), while 1 exhibited only a 160-fold decreased d agonism (10) and the d antagonism of 8 enhanced >10-fold (pA2=10.62, 80); and (ii) a consistent loss of m-affinity resulted in enhanced d-opioid receptor selectivity. With the exception of compound 10, the change in the hydrophobic environment at the N-terminus and formation of a tertiary amine by N,N-dimethylation in analogues of the Dmt-Tic pharmacophore produced potent d-selective antagonists