Novel multiple opioid ligands based on 4-aminobenzazepinone (Aba), azepinoindole (Aia) and tetrahydroisoquinoline (Tic) scaffolds

Abstract

The dimerization and trimerization of the Dmt-Tic, Dmt-Aia and Dmt-Aba pharmacophores provided multiple ligands which were evaluated in vitro for opioid receptor binding and functional activity. Whereas the Tic- and Aba multimers proved to be dual and balanced delta/mu antagonists, as determined by the functional [S(35)]GTPgammaS binding assay, the dimerization of potent Aia-based 'parent' ligands unexpectedly resulted in substantial less efficient receptor binding and non-active dimeric compounds.

Figure 1

General representation of bifunctional ligands 1 and literature examples 2 to 4

Figure 2

Structures of H-Dmt-Tic-OH 5, H-Dmt-Aba-Gly-NH-Bn 6, H-Dmt-D-Aia-Gly-NH-Bn 7 and Me₂Dmt-L-AiaGly-OH 8 pharmacophores and synthesis of bifunctional ligands 9 to 16

Figure 3

Effect of Dmt-Tic-dimer 9 on Loperamide and deltorphin C stimulated GTPγS binding in SK-N-SH and NG108-15 cell membranes, respectively.