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

  • Bioorg Med Chem Lett. 2015 Nov 15;25(22):5393-7. doi: 10.1016/j.bmcl.2015.09.025.
Xin Liu  1 ,  Long Zhao  1 ,  Yuan Wang  1 ,  Lingyun Mou  1 ,  Junxian Yang  1 ,  Yixin Zhang  1 ,  Dan Wang  1 ,  Rui Wang  2
Affiliations
  • 1. Department of pharmacology, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, School of Life Science, Lanzhou University, Lanzhou 730000, PR China.
  • 2. Department of pharmacology, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, School of Life Science, Lanzhou University, Lanzhou 730000, PR China. Electronic address: [email protected].
PMID: 26403932 DOI: 10.1016/j.bmcl.2015.09.025
Abstract

We synthesized two novel endomorphin-1 (EM-1) analogs by substituting the C-terminus residue with (thienyl)-α-methylene-β-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.

Keywords
Analgesia; Blood–brain barrier; Endomorphin; Unnatural amino acid.