Relationship between structure and P-glycoprotein inhibitory activity of dimeric peptides related to the Dmt-Tic
Akihiro Ambo1, Hiromichi Ohkatsu, Motoko Minamizawa
1Tohoku Pharmaceutical University, Aoba-ku, Sendai, Japan.
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.
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