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

Abstract

To improve the oral bioavailability of a dermorphin tetrapeptide analog, N^α-1-iminoethyl-Tyr-D-MetO-Phe-MeβAla-OH (III),¹⁾ 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 Tyr¹. 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 ED₅₀(p.o.)/ED₅₀(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 ED₅₀(p.o.)/ED₅₀(s.c.) ratio equivalent to that of morphine was found for an acetylated derivative, N^α-1-iminoethyl-Tyr(COMe)-D-MetO-Phe-MeβAla-OH (7a), as well as for a methoxycarbonylated derivative, N^α-1-iminoethyl-Tyr(CO₂Me)-D-MetO-Phe-MeβAla-OH (7l).