title: 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(alpha)-1-iminoethyl-Tyr-D-MetO-Phe-MebetaAla-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 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(alpha)-1-iminoethyl-Tyr(COMe)-D-MetO-Phe-MebetaAla-OH (7a), as well as for a methoxycarbonylated derivative, N(alpha)-1-iminoethyl-Tyr(CO2Me)-D-MetO-Phe-MebetaAla-OH (7l).
authors.affiliation: Research Institute, Daiichi Fine Chemical Co., Ltd, Takaoka, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Ogawa
authors.forename: Mamoru
authors.initials: M
authors.lastname: Araki
authors.forename: Tetsuhisa
authors.initials: T
authors.lastname: Miyamae
authors.forename: Toru
authors.initials: T
authors.lastname: Okayama
authors.forename: Masaki
authors.initials: M
authors.lastname: Hagiwara
authors.forename: Shinobu
authors.initials: S
authors.lastname: Sakurada
authors.forename: Tadanori
authors.initials: T
authors.lastname: Morikawa
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D000818:Animals; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D004951:Esterification; D051379:Mice; D018847:Opioid Peptides / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods
chemical_list: D000700:Analgesics; D018847:Opioid Peptides