Small molecule modulation of p75 neurotrophin receptor functions.

Ligand-independent and/or proNGF-induced p75(NTR) signaling has emerged as a potential major contributor to a number of pathological states, including axotomy-induced death, motor neuron degeneration, neuronal degeneration in Alzheimer's disease and oligodendrocyte death following spinal cord injury. A long standing goal in the neurotrophin field has been the development of non-peptide, small molecules capable of functioning as specific ligands at neurotrophin receptors such as p75(NTR) to promote desired biological outcomes. Synthetic peptides modeled on neurotrophin protein domains have been found to bind to and activate various neurotrophin receptors, raising the possibility that active, non-peptide, small molecule ligands might also be identified; however, traditional high-throughput screening approaches have been largely ineffective in identifying such compounds. Using pharmacophores derived from the structure of loop 1 of nerve growth factor, non-peptide, small molecules that function as p75(NTR) ligands to promote survival and block proNGF-induced death have recently been identified. Small molecule p75(NTR) ligands, with high potency and specificity, may provide novel therapeutic approaches for neurodegenerative diseases, neurotrauma and other pathologic states.