Design, Synthesis, Pharmacological Evaluation, and Structure-Activity Study of Novel Endomorphin Analogues with Multiple Structural Modifications

Abstract: This study reports on new proteolytically stable, pharmacologically active endomorphin analogues, incorporating Dmt(1), Achc(2), pFPhe(4), or beta MePhe(4) unnatural amino acids. Consistent with earlier results, it was found that the analogues carrying anti and Achc2 residues displayed the highest p-opioid receptor affinities, depending upon the configuration of the incorporated Achc(2). Combination of such derivatives with pFPhe(4) or beta MePhe(4) yielded further compounds with variable binding potencies. Combined application of Dmt(1), cis-(1S,2R)Achc(2), and pFPhe(4) (compound 16) resulted in the most potent analogue. Ligand stimulated [S-35]GTP gamma S binding assays indicated that the analogues retained their agonist activities and opioid receptor specificities. NMR and molecular modeling studies of the analogues containing beta MePhe(4) or pFPhe(4) confirmed the predominance of bent structures, however, it is apparent that bent structures are energetically more favored than random/extended structures for all studied compounds.