Chain branching approach in structure modification of TRPV1 receptor antagonist MK056 and its analogs.

A series of chain branched 1,3-dibenzylthiourea derivatives were designed, synthesized, and evaluated for their antagonist activity against TRPV1. The synthesized chain branched 1,3-dibenzylthioureas 9a-g were tested for their antagonist activities against TRPV1 by (45)Ca(2+)-influx assay using neonatal rat cultured spinal sensory neurons. Fluorinated ethyl-branched analog 9g showed the most potent antagonist activity with an IC(50) value of 0.41 μM, but all of the chain branched analogs were less potent than the parent compounds MK-056 and SC-0030, indicating that chain branching on the benzylic position of B-ring is detrimental to potency. Optimized receptor binding seems to be interfered by chain branching, and resulted in decrease in potency.