Conclusions

Medicinal Chemistry Group: Drug Development

Our results were the first demonstration of the conversion of a peptidic δ-opioid receptor antagonist into a δ-agonist and that several analogues exhibited bifunctional activities for the δ- and µ-opioid receptor. Similar conversions in the activity of several non-peptide substances were observed. Interestingly, in bifunctional analogues with high µ-affinities, N,N-dimethylation drastically reduced binding affinity. Extension from the C-terminus of Tic with bulky hydrophobic groups, such as 1-adamantane and tert-butyl, as well as with benzimidazole provided evidence that a highly δ-selective opioid ligand could also exhibit high µ-opioid receptor affinity and µ-opioid agonism.

Our data with bis-[Dmt-NH]-alkyl derivatives permitted a corollary theory on the concept of ligand determinants. The questions raised were, for example, what constitutes a distinct message and an address domain in an opioid ligand? What are the important structural elements of the ligand required for receptor biding? Although those opioidmimetics were symmetric, they behaved as if they consisted of two distinct structural domains. This suggested that the receptor contains two hydrophobic regions, which are equally accessible to Dmt: presumably the aromatic ring interacts through π-π interactions or ring stacking with receptor residues. The methyl groups on the tyramine ring and the interposing alkyl chain keep the ligand anchored. Furthermore, the flexible linker might conform to the change in pocket dimensions formed by different regions of the transmembrane helices of the membrane-imbedded receptor.