Small-molecule modulation of neurotrophin receptors: a strategy for the treatment of neurological disease

Nat Rev Drug Discov. 2013 Jul;12(7):507-25. doi: 10.1038/nrd4024.


Neurotrophins and their receptors modulate multiple signalling pathways to regulate neuronal survival and to maintain axonal and dendritic networks and synaptic plasticity. Neurotrophins have potential for the treatment of neurological diseases. However, their therapeutic application has been limited owing to their poor plasma stability, restricted nervous system penetration and, importantly, the pleiotropic actions that derive from their concomitant binding to multiple receptors. One strategy to overcome these limitations is to target individual neurotrophin receptors — such as tropomyosin receptor kinase A (TRKA), TRKB, TRKC, the p75 neurotrophin receptor or sortilin — with small-molecule ligands. Such small molecules might also modulate various aspects of these signalling pathways in ways that are distinct from the programmes triggered by native neurotrophins. By departing from conventional neurotrophin signalling, these ligands might provide novel therapeutic options for a broad range of neurological indications.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Animals
  • Clinical Trials as Topic
  • Drug Discovery / methods*
  • Humans
  • Ligands
  • Molecular Targeted Therapy / methods*
  • Nerve Growth Factors / biosynthesis
  • Nerve Growth Factors / metabolism
  • Nerve Growth Factors / therapeutic use
  • Nervous System Diseases / drug therapy*
  • Nervous System Diseases / metabolism
  • Nervous System Diseases / pathology
  • Receptors, Nerve Growth Factor / metabolism*
  • Signal Transduction
  • Small Molecule Libraries / pharmacology
  • Small Molecule Libraries / therapeutic use*


  • Ligands
  • Nerve Growth Factors
  • Receptors, Nerve Growth Factor
  • Small Molecule Libraries