| Abstract
| - Analogues of the 2‘,6‘-dimethyl-l-tyrosine (Dmt)−1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid (Tic) pharmacophore were prepared to test the hypothesis that a “spacer” and a thirdaromatic center in opioid peptides are required to convert a δ-antagonist into ligands withδ-agonist or with mixed δ-antagonist/μ-agonist properties. Potent δ-agonists and bifunctionalcompounds with high δ- and μ-opioid receptor affinities were obtained by varying the spacerlength [none, NH−CH2, NH−CH2−CH2, Gly−NH−CH2] and C-terminal aromatic nucleus [1H-benzimidazole-2-yl, phenyl (Ph) and benzyl groups]. C-terminal modification primarily affectedμ-opioid receptor affinities, which increased maximally 1700-fold relative to the prototypeδ-antagonist H−Dmt−Tic−NH2 and differentially modified bioactivity. In the absence of aspacer (1), the analogue exhibited dual δ-agonism (pEC50, 7.28) and δ-antagonism (pA2, 7.90).H−Dmt−Tic−NH−CH2−1H-benzimidazol-2-yl (Bid) (2) became a highly potent δ-agonist(pEC50, 9.90), slightly greater than deltorphin C (pEC50, 9.56), with μ-agonism (pE50, 7.57),while H−Dmt−Tic−Gly−NH−CH2−Bid (4) retained potent δ-antagonism (pA2, 9.0) but withan order of magnitude less μ-agonism. Similarly, H−Dmt−Tic−Gly−NH−Ph (5) had nearlyequivalent high δ-agonism (pEC50, 8.52) and μ-agonism (pEC50, 8.59), while H−Dmt−Tic−Gly−NH−CH2−Ph (6) whose spacer was longer by a single methylene group exhibited potentδ-antagonism (pA2, 9.25) and very high μ-agonism (pEC50, 8.57). These data confirm that thedistance between the Dmt−Tic pharmacophore and a third aromatic nucleus is an importantcriterion in converting Dmt−Tic from a highly potent δ-antagonist into a potent δ-agonist orinto ligands with mixed δ- and μ-opioid properties.
|
