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This study reports on new proteolytically stable, pharmacologically active endomorphin analogues, incorporating Dmt¹, Achc², pFPhe⁴, or βMePhe⁴ unnatural amino acids. Consistent with earlier results, it was found that the analogues carrying Dmt¹ and Achc² residues displayed the highest μ-opioid receptor affinities, depending upon the configuration of the incorporated Achc². Combination of such derivatives with pFPhe⁴ or βMePhe⁴ yielded further compounds with variable binding potencies. Combined application of Dmt¹, cis-(1S,2R)Achc², and pFPhe⁴ (compound 16) resulted in the most potent analogue. Ligand stimulated [³⁵S]GTPγS binding assays indicated that the analogues retained their agonist activities and opioid receptor specificities. NMR and molecular modeling studies of the analogues containing βMePhe⁴ or pFPhe⁴ confirmed the predominance of bent structures, however, it is apparent that …