title: 4-Biphenyl and 2-naphthyl substituted 6,7-dimethoxytetrahydroisoquinoline derivatives as potent P-gp modulators.
abstract: Starting from lead compound 1 (EC(50)=1.64 microM), 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 (clogP) were correlated with the P-gp inhibiting activity of tested compounds. In the biphenyl series, derivative 4d displayed the best results (EC(50)=0.05 microM). The corresponding amide 3d was found less active (EC(50)=3.5 microM) 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.
authors.affiliation: Dipartimento Farmacochimico, Università degli Studi di Bari, via Orabona, 4, 70125 Bari, Italy. colabufo@farmchim.uniba.it
authors.forename: Nicola Antonio
authors.initials: NA
authors.lastname: Colabufo
authors.forename: Francesco
authors.initials: F
authors.lastname: Berardi
authors.forename: Mariangela
authors.initials: M
authors.lastname: Cantore
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Perrone
authors.forename: Marialessandra
authors.initials: M
authors.lastname: Contino
authors.forename: Carmela
authors.initials: C
authors.lastname: Inglese
authors.forename: Mauro
authors.initials: M
authors.lastname: Niso
authors.forename: Roberto
authors.initials: R
authors.lastname: Perrone
authors.forename: Amalia
authors.initials: A
authors.lastname: Azzariti
authors.forename: Grazia Maria
authors.initials: GM
authors.lastname: Simone
authors.forename: Angelo
authors.initials: A
authors.lastname: Paradiso
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008055:Lipids / Q000737:chemistry; D015394:Molecular Structure; D009284:Naphthols / Q000737:chemistry*; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C528603:6,7-dimethoxytetrahydroisoquinoline; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001713:Biphenyl Compounds; D008024:Ligands; D008055:Lipids; D009284:Naphthols; D044005:Tetrahydroisoquinolines