Synthesis and antinociceptive activity of orally active opioid peptides: improvement of oral bioavailability by esterification
| Autor: | Shinobu Sakurada, Tadashi Ogawa, Masaki Hagiwara, Tadanori Morikawa, Toru Okayama, Tetsuhisa Miyamae, Mamoru Araki |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Analgesics
Tetrapeptide Dose-Response Relationship Drug Esterification Chemistry Stereochemistry Administration Oral Biological Availability General Chemistry General Medicine Dermorphin Chemical synthesis Bioavailability Acylation chemistry.chemical_compound Mice Pharmacokinetics Opioid Peptides Oral administration Drug Discovery Lipophilicity Animals Pain Measurement |
| Zdroj: | Chemicalpharmaceutical bulletin. 51(7) |
| ISSN: | 0009-2363 |
| Popis: | 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). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|