Opioid pseudopeptides containing heteroaromatic or heteroaliphatic nuclei

In lieu of H-Dmt-Tic-OH, H-Dmt-analogues included 2-amino-3(1H-benzoimidazol-2-yl)-propionic acid, N(Bzl)Gly, L-octahydroindole-2-carboxylic acid, [3S-(3α,4aβ,8aβ)]-decahydro-3-isoquinoline carboxylic acid, benzimidazole-, pyridoindole- or spiroinden-derivatives, or C-terminally modified. L- or D-Ala, Sar, or Pro were spacers between aromatic nuclei. Only H-Dmt-(Xaa-)-pyridoindole exhibited high affinities with δ and μ antagonism. The peptides competed equally against [3H]DPDPE (δ agonist) or [3H]N,N(CH3)2-Dmt-Tic-OH (δ antagonist) signaling a single δ binding site. The data confirm the importance of Tic for δ affinity and antagonism, while heterocyclic or heteroaliphatic nuclei, or spacer exert effects on μ- and δ-receptor properties.