Design, synthesis, and evaluation of new endomorphin analogs with enhanced central antinociception after peripheral administration.

We synthesized two novel endomorphin-1 (EM-1) analogs by substituting the C-terminus residue with (thienyl)-α-methylene-ß-amino acids (Map). Several in vitro and in vivo assays were used to determine the activity of the analogs. The two EM-1 analogs showed subnanomolar binding affinity and functional activity at the µ-opioid receptor in HEK293 cells. Tail-flick and formalin tests further revealed that the EM-1 analogs were very effective after intravenous administration. Our results indicate that compared to endomorphin-1, the (thienyl)Map modified peptides showed improved blood-brain barrier permeability.