Small molecule Trk receptor agonists and other neurotrophic factor mimetics.

Abstract

Nerve growth factor belongs to a small family of proteins whose binding at the Trk and p75(NTR) transmembrane receptors triggers a cascade of signaling events that give rise to neurotrophic responses in neuronal cells and in vivo. Following their robust effects in animal models of neurodegeneration, neurotrophins have been evaluated for therapy for several human neurodegenerative diseases. However, due mainly to the poor pharmacokinetic behavior of these proteins, they have largely met without success in the clinic, making it desirable to develop small molecule neurotrophin mimetics. A range of compounds is described that achieves some of the neurotrophic and neuroprotective effects attributed to neurotrophins through a variety of mechanisms. These small molecules are divided into the following functional categories: (1). compounds that activate Trk receptors directly; (2). compounds that potentiate the actions of neurotrophins on Trk receptors; (3). compounds that activate Trk indirectly; (4). compounds that influence neurotrophin expression or secretion; and (5). a broad class of compounds that act downstream of, or independently of, Trk receptors. Unfortunately, most of the compounds that have been reported suffer from either lack of specificity for the desired mechanism/effect(s) or lack of efficacy of the compounds in appropriate in vivo models, or both. This second limitation has been particularly severe for compounds designed to mimic the neurotrophins in their interaction with Trk receptors, an ongoing and formidable challenge. Nevertheless, a small subset of the compounds, acting on intracellular signaling pathways downstream of Trk receptors, shows promise for the future treatment of neurodegenerative diseases.