4-Biphenyl and 2-naphthyl substituted 6,7-dimethoxytetrahydroisoquinoline derivatives as potent P-gp modulators

Nicola Antonio Colabufo, Francesco Berardi, Mariangela Cantore, Maria Grazia Perrone, Marialessandra Contino, Carmela Inglese, Mauro Niso, Roberto Perrone, Amalia Azzariti, Grazia Maria Simone, Angelo Paradiso

Research output: Contribution to journalArticlepeer-review


Starting from lead compound 1 (EC50 = 1.64 μM), its non-basic nucleus has been conformationally restricted by 4-biphenyl and 2-naphthyl moieties. In each series we investigated if the presence of H-bond donor or acceptor substituents, the basicity and the lipophilicity (c log P) were correlated with the P-gp inhibiting activity of tested compounds. In the biphenyl series, derivative 4d displayed the best results (EC50 = 0.05 μM). The corresponding amide 3d was found less active (EC50 = 3.5 μM) ascertaining the importance of basicity in this series whilst the presence of hydroxy or methoxy substituents seems to be negligible. In the naphthyl series, both the basicity and the presence of H-bond donor or acceptor groups seem to be negligible. Moreover, the lipophilicity did not influence the P-gp inhibition activity of each series. Specific biological assays have been carried out to establish the P-gp interacting mechanism of tested compounds discriminating between substrates and inhibitors. Moreover, compound 4d displayed a potent P-gp inhibition activity with good selectivity towards BCRP pump.

Original languageEnglish
Pages (from-to)3732-3743
Number of pages12
JournalBioorganic and Medicinal Chemistry
Issue number7
Publication statusPublished - Apr 1 2008


  • 2-Naphthyl-6,7-dimethoxytetrahydroisoquinoline
  • 4-Biphenyl-6,7-dimethoxytetrahydroisoquinoline
  • BCRP
  • P-glycoprotein

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science


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