title: Deconstruction of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline moiety to separate P-glycoprotein (P-gp) activity from σ2 receptor affinity in mixed P-gp/σ2 receptor agents.
abstract: 6,7-Dimethoxytetrahydroisoquinoline is widely used as basic moiety in σ2 receptor ligands, in order to provide σ2versus σ1 selectivity. This same moiety is also widely exploited in modulators of P-glycoprotein (P-gp) efflux pump, so that mixed σ2/P-gp agents are often obtained. Deconstruction of 6,7-dimethoxytetrahydroisoquinoline moiety present in the potent mixed σ2/P-gp agent 6,7-dimethoxy-2-[4-[1-(4-fluorophenyl)-1H-indol-3-yl]butyl]-1,2,3,4-tetrahydroisoquinoline (1) could lead to the separation of σ2 affinity from P-gp activity. Therefore, phenethylamino-, benzylamino- and indanamine series were obtained. The NH group was also methylated in the N-phenethylamino series, and ethylated in the benzylamino series, to better match 6,7-dimethoxytetrahydroisoquinoline. The σ2 affinity drastically decreased with the increase of conformational freedom, whereas alkylation of the NH-group was beneficial for σ2 receptor interaction. By contrast, deconstruction of 6,7-dimethoxytetrahydroisoquinoline slightly reduced P-gp activity, with dimethoxy-substituted derivatives displaying potent P-gp interaction. Therefore, 'ring-opened' 6,7-dimethoxytetrahydroisoquinoline derivatives represent a promising strategy to obtain P-gp selective agents devoid of σ2 receptor affinity.
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, Via Orabona 4, I-70125 Bari, Italy.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Pati
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, Via Orabona 4, I-70125 Bari, Italy. Electronic address: carmen.abate@uniba.it.
authors.forename: Carmen
authors.initials: C
authors.lastname: Abate
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, Via Orabona 4, I-70125 Bari, Italy.
authors.forename: Marialessandra
authors.initials: M
authors.lastname: Contino
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, Via Orabona 4, I-70125 Bari, Italy.
authors.forename: Savina
authors.initials: S
authors.lastname: Ferorelli
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, Via Orabona 4, I-70125 Bari, Italy.
authors.forename: Renzo
authors.initials: R
authors.lastname: Luisi
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, Via Orabona 4, I-70125 Bari, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Carroccia
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, Via Orabona 4, I-70125 Bari, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Niso
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, Via Orabona 4, I-70125 Bari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Berardi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004285:Dogs; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D017480:Receptors, sigma / Q000378:metabolism*; D044005:Tetrahydroisoquinolines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C528603:6,7-dimethoxytetrahydroisoquinoline; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017480:Receptors, sigma; D044005:Tetrahydroisoquinolines; C106107:sigma-2 receptor
keywords: 6,7-Dimethoxytetrahydroisoquinoline; Conformational analysis; P-glycoprotein; σ(2) receptor