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

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.