title: Tetrahydroisoquinoline-Derived Urea and 2,5-Diketopiperazine Derivatives as Selective Antagonists of the Transient Receptor Potential Melastatin 8 (TRPM8) Channel Receptor and Antiprostate Cancer Agents.
abstract: Tetrahydroisoquinoline derivatives containing embedded urea functions were identified as selective TRPM8 channel receptor antagonists. Structure-activity relationships were investigated, with the following conclusions: (a) The urea function and the tetrahydroisoquinoline system are necessary for activity. (b) Bis(1-aryl-6,7dimethoxy-1,2,3,4-tetrahydroisoquinolyl)ureas are more active than compounds containing one tetrahydroisoquinoline ring and than an open phenetylamine ureide. (c) Trans compounds are more active than their cis isomers. (d) Aryl substituents are better than alkyls at the isoquinoline C-1 position. (e) Electron-withdrawing substituents lead to higher activities. The most potent compound is the 4-F derivative, with IC50 in the 10(-8) M range and selectivities around 1000:1 for most other TRP receptors. Selected compounds were found to be active in reducing the growth of LNCaP prostate cancer cells. TRPM8 inhibition reduces proliferation in the tumor cells tested but not in nontumor prostate cells, suggesting that the activity against prostate cancer is linked to TRPM8 inhibition.
authors.affiliation: Endocannabinoid Research Group, Institute of Protein Biochemistry and Institute of Applied Sciences & Intelligent Systems, National Research Council , Via Campi Flegrei 34, Comprensorio Olivetti, 80078 Pozzuoli, Naples, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: De Petrocellis
authors.affiliation: Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense , 28040 Madrid, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Arroyo
authors.affiliation: Endocannabinoid Research Group, Institute of Protein Biochemistry, National Research Council , Via P. Castellino 111, 80131 Naples, Italy.
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Orlando
authors.affiliation: Endocannabinoid Research Group, Institute of Protein Biochemistry and Institute of Applied Sciences & Intelligent Systems, National Research Council , Via Campi Flegrei 34, Comprensorio Olivetti, 80078 Pozzuoli, Naples, Italy.
authors.forename: Aniello
authors.initials: A
authors.lastname: Schiano Moriello
authors.affiliation: Endocannabinoid Research Group, Institute of Protein Biochemistry and Institute of Applied Sciences & Intelligent Systems, National Research Council , Via Campi Flegrei 34, Comprensorio Olivetti, 80078 Pozzuoli, Naples, Italy.
authors.forename: Rosa Maria
authors.initials: RM
authors.lastname: Vitale
authors.affiliation: Endocannabinoid Research Group, Institute of Protein Biochemistry and Institute of Applied Sciences & Intelligent Systems, National Research Council , Via Campi Flegrei 34, Comprensorio Olivetti, 80078 Pozzuoli, Naples, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Amodeo
authors.affiliation: Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense , 28040 Madrid, Spain.
authors.forename: Aránzazu
authors.initials: A
authors.lastname: Sánchez
authors.affiliation: Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense , 28040 Madrid, Spain.
authors.forename: Cesáreo
authors.initials: C
authors.lastname: Roncero
authors.affiliation: Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense , 28040 Madrid, Spain.
authors.forename: Giulia
authors.initials: G
authors.lastname: Bianchini
authors.affiliation: S.D. Química Analítica, Facultad de Farmacia, Universidad Complutense , 28040 Madrid, Spain.
authors.forename: M Antonia
authors.initials: MA
authors.lastname: Martín
authors.affiliation: Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense , 28040 Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: López-Alvarado
authors.affiliation: Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense , 28040 Madrid, Spain.
authors.forename: J Carlos
authors.initials: JC
authors.lastname: Menéndez
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D054659:Diketopiperazines / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013329:Structure-Activity Relationship; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D054659:Diketopiperazines; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; D044005:Tetrahydroisoquinolines; C014843:1,2,3,4-tetrahydroisoquinoline; D014508:Urea; D002118:Calcium