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.

Novel selective, potent naphthyl TRPM8 antagonists identified through a combined ligand- and structure-based virtual screening approach

“…Known TRPM8 antagonists primarily belong to the chemical classes of para-menthane-based or non-para-menthane-based ligands 21 – 23 , depending on the presence of the menthol scaffold. Many of these TRPM8 antagonists, such as BCTC 24 , CTPC 25 , and capsazepine 26 are also antagonists of other TRP channels, particularly TRPV1 and TRPA1, thus suggesting a conserved mechanism for the ligand activation of these thermosensitive TRP channels 27 – 30 . This overlapping mechanism of activation makes the identification of selective agents for these ion channels difficult.…”

“…This overlapping mechanism of activation makes the identification of selective agents for these ion channels difficult. To date, only three TRPM8 antagonists have reached clinical evaluation: the quinolone- and pyridine-carboxamide derivatives PF-05105679 (Pfizer; ClinicalTrials.gov Identifier: NCT01393652) and AMG-333 (AMGEN; ClinicalTrials.gov Identifier: NCT01953341), which entered but did not pass phase I studies 30 , 31 , and the cannabinoid Cannabidivarin (GWP-42006) (GW Pharmaceuticals; ClinicalTrials.gov Identifier: NCT02365610), which is currently in phase II clinical study 31 , 32 . Thus, the need for novel TRPM8 inhibitors is urgent and many companies and researchers are working on this target.…”

Transient Receptor Potential Cation Channels in Cancer Therapy

“…Menthol-induced MMP-9 activity is also suppressed by RQ-00203078 [54]. In addition, recently, tetrahydroisoquinoline-derived urea and 2,5-Diketopiperazine derivatives as selective antagonists of TRPM8 with high anti-PCa activity (at 10 nM) were synthetized by the De Petrocellis and colleagues [58].…”

Isolation and Structural Characterization of Bioactive Molecules on Prostate Cancer from Mayan Traditional Medicinal Plants

“…As an example, different plant extracts and herbal compounds studied in traditional Chinese medicine showed promising anti-prostate cancer activity [ 4 ]. Indeed, many clinically successful anti-cancer drugs are either natural products themselves or have been developed from natural occurring lead compounds [ 5 , 6 ]. One example used in the therapy of prostate cancer (PCa) is docetaxel [ 7 ].…”