New Templates for Syntheses of Ring-Fused, C¹⁰ β-Turn Peptidomimetics Leading to the First Reported Small-Molecule Mimic of Neurotrophin-3

Abstract

beta-Turn peptidomimetics 1 were designed to mimic hot spots of neurotrophin-3 (NT-3) and others. Solid-phase syntheses of these were developed, though limitations were encountered with scale-up. Consequently, an alternative design with 2 was investigated. 1 and 2 favored distorted type I beta-turn conformations in solution. It was found that peptidomimetic 2b has NT-3-like neurotrophic activity in cell survival assays, selectively binds the NT-3 receptor TrkC, and induces the tyrosine phosphorylation of the TrkC receptor.