Synthesis and Antinociceptive Activity of Orally Active Opioid Peptides: Improvement of Oral Bioavailability by Esterification

概要

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To improve the oral bioavailability of a dermorphin tetrapeptide analog, N^α-1-iminoethyl-Tyr-D-MetO-Phe-MeβAla-OH (III), which has a potent analgesic activity after oral administration, various derivatives were synthesized to increase lipophilicity by esterification of the C-terminal carboxyl group and/or acylation of the phenolic hydroxyl group on Tyr^1. Antinociceptive activity was evaluated after subcutaneous or oral administration using the mouse tail pressure test. As a result, increased antinociceptive activity after oral administration as well as an improved ED_<50>(p.o.)/ED_<50>(s.c.) ratio, which is an indicator of oral bioavailability, were found for some compounds. With regard to the improvement of bioavailability, derivatives with acylation of the phenolic hydroxyl group on Tyr1 showed better results than derivatives with esterification of the C-terminal carboxyl group. In particular, an ED_<50>(p.o.)/ED_<50>(s.c.) ratio equivalent to that of morphine was found for an acetylated derivative ,N^α-l-iminoethyl-Tyr(COMe)-D-MetO-Phe-MeβAla-OH (7a), as well as for a methoxycarbonylated derivative, N^α-1-iminoethyl-Tyr(CO_2Me)-D-MetO-Phe-MeβAla-OH(71).
社団法人日本薬学会の論文
2003-07-01