Insights Into the Molecular Mechanism of Triptan Transport by P-glycoprotein.
J Pharm Sci
; 106(6): 1670-1679, 2017 06.
Article
em En
| MEDLINE
| ID: mdl-28283434
ABSTRACT
The P-glycoprotein (Pgp) transporter reduces the penetration of a chemically diverse range of neurotherapeutics at the blood-brain barrier, but the molecular features of drugs and drug-Pgp interactions that drive transport remain to be clarified. In particular, the triptan neurotherapeutics, eletriptan (ETT) and sumatriptan (STT), were identified to have a >10-fold difference in transport rates despite being from the same drug class. Consistent with these transport differences, ETT activated Pgp-mediated ATP hydrolysis â¼2-fold, whereas STT slightly inhibited Pgp-mediated ATP hydrolysis by â¼10%. The interactions between them were also noncompetitive, suggesting that they occupy different binding sites on the transporter. Despite these differences, protein fluorescence spectroscopy revealed that the drugs have similar affinity to the transporter. NMR with Pgp and the drugs showed that they have distinct interactions with the transporter. Tertiary conformational changes probed by acrylamide quenching of Pgp tryptophan fluorescence with the drugs and a nonhydrolyzable ATP analog implied that the STT-bound Pgp must undergo larger conformational changes to hydrolyze ATP than ETT-bound Pgp. These results and previous transport studies were used to build a conformationally driven model for triptan transport with Pgp where STT presents a higher conformational barrier for ATP hydrolysis and transport than ETT.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pirrolidinas
/
Triptaminas
/
Agonistas do Receptor de Serotonina
/
Sumatriptana
/
Membro 1 da Subfamília B de Cassetes de Ligação de ATP
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article