title: Analogues of σ receptor ligand 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28) with added polar functionality and reduced lipophilicity for potential use as positron emission tomography radiotracers.
abstract: 1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine 1 (PB28) represents an excellent lead candidate for therapeutic and/or diagnostic applications in oncology. However, because its utility is limited by its relatively high degree of lipophilicity, novel analogues of 1 with reduced lipophilic character were designed by substituting methylene groups with more polar functional groups in the propylene linker and at the tetralin C4 position. For the chiral analogues, separate enantiomers exhibited substantial and roughly equal affinities within a given receptor subtype, with the greatest difference observed for compound 9 at σ(1) (7.5-fold; (-)-(S)-9 K(i) = 94.6 nM, (+)-(R)-9 K(i) = 12.6 nM). Compound (-)-(S)-9 was also found to be the most σ(2)-selective agent (σ(2) K(i) = 5.92 nM), to possess a lipophilicity consistent with entry into tumor cells (log D(7.4) = 2.38), and to show minimal antiproliferative activity. However, (-)-(S)-9 exhibited moderate activity (EC(50) = 8.1 μM) at the P-gp efflux pump.
authors.affiliation: Dipartimento Farmacochimico, Università degli Studi di Bari Aldo Moro, Via Orabona 4, I-70125 Bari, Italy. abate@farmchim.uniba.it
authors.forename: Carmen
authors.initials: C
authors.lastname: Abate
authors.forename: Mauro
authors.initials: M
authors.lastname: Niso
authors.forename: Enza
authors.initials: E
authors.lastname: Lacivita
authors.forename: Philip D
authors.initials: PD
authors.lastname: Mosier
authors.forename: Annamaria
authors.initials: A
authors.lastname: Toscano
authors.forename: Roberto
authors.initials: R
authors.lastname: Perrone
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D009904:Optical Rotation; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D049268:Positron-Emission Tomography / Q000379:methods*; D017480:Receptors, sigma / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013499:Surface Properties; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008024:Ligands; C513937:PB28 compound; D010879:Piperazines; D017480:Receptors, sigma; D013764:Tetrahydronaphthalenes