Pyrazolopyrimidines as Potent Stimulators for Transient Receptor Potential Canonical 3/6/7 Channels

Transient receptor potential canonical
3/6/7 (TRPC3/6/7) are highly
homologous receptor-operated nonselective cation channels. Despite
their physiological significance, very few selective and potent agonists
are available for functional examination of these channels. Using
a cell-based high throughput screening approach, a lead compound with
the pyrazolopyrimidine skeleton was identified as a TRPC6 agonist.
Synthetic schemes for the lead and its analogues were established,
and structural–activity relationship studies were carried out.
A series of potent and direct agonists of TRPC3/6/7 channels were
identified, and among them, 4m–4p have a potency order of TRPC3 > C7 > C6, with 4n being
the most potent with an EC50 of <20 nM on TRPC3. Importantly,
these compounds exhibited no stimulatory activity on related TRP channels.
The potent and selective compounds described here should be suitable
for evaluation of the roles of TRPC channels in the physiology and
pathogenesis of diseases, including glomerulosclerosis and cancer.