TRPV1 modulators: Structure-activity relationships using a rational combinatorial approach

A discrete library of linear and hydantoin-containing dipeptide derivatives, based on the Lys-Trp(Nps) scaffold, was prepared by solid-phase synthesis. SAR studies indicated that potency for TRPV1 blockade and selectivity towards NMDA is mainly dictated by the side-chain length and the basic nature of ?, ?-groups in the N-terminal residue. The 2-Nps moiety at position 2 of Trp indole ring is preferred over the 2-pyridine one.