title: Relationship between structure and P-glycoprotein inhibitory activity of dimeric peptides related to the Dmt-Tic pharmacophore.
abstract: To develop novel inhibitors of P-glycoprotein (P-gp), dimeric peptides related to an opioid peptide containing the Dmt-Tic pharmacophore were synthesized and their P-gp inhibitory activities were analyzed. Of the 30 analogs synthesized, N(α),N(ε)-[(CH(3))(2)Mle-Tic](2)Lys-NH(2) and its D-Lys analog were found to exhibit potent P-gp inhibitory activity, twice that of verapamil, in doxorubicin-resistant K562 cells. Structure-activity studies indicated that the correct hydrophobicity and spacer length between two aromatic rings are important structural elements in this series of analogs for inhibition of P-gp.
authors.affiliation: Tohoku Pharmaceutical University, Aoba-ku, Sendai, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ambo
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Ohkatsu
authors.forename: Motoko
authors.initials: M
authors.lastname: Minamizawa
authors.forename: Hideko
authors.initials: H
authors.lastname: Watanabe
authors.forename: Shigeki
authors.initials: S
authors.lastname: Sugawara
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nitta
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tsuda
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Okada
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sasaki
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001692:Biological Transport; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D060327:Solid-Phase Synthesis Techniques; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: C446951:2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004151:Dipeptides; D044005:Tetrahydroisoquinolines; D004317:Doxorubicin; D014700:Verapamil