Synthesis and biological activity of N-methylated analogs of endomorphin-2

In this paper, we describe the synthesis of a series of endomorphin-2 analogs containing N-methylated amino acids. [Sar 2]endomorphin-2 had the highest μ-receptor affinity and showed the strongest analgesic effect when administered centrally and peripherally. In this paper, we describe the synthesis of a series of endomorphin-2 analogs containing N-methylated amino acids, consecutively in each position. The μ-opioid receptor binding affinities of the new analogs were determined in the displacement experiments. Their in vivo antinociceptive activity was assessed in the hot-plate test in mice after central (icv) and peripheral (ip) administration. [Sar 2]endomorphin-2, which had the highest μ-receptor affinity, also showed the strongest analgesic effect when administered centrally and was the only analog that retained activity after peripheral injection.