Neurotrophin Small Molecule Mimetics: Candidate Therapeutic Agents for Neurological Disorders

Neurotrophin proteins bind to p75NTR and Trk receptors to trigger potent biological effects including modulation of neuronal survival, promotion and maintenance of neurite networks, upregulation of neural function and modulation of synaptic plasticity. Factors limiting clinical application include poor stability, restricted nervous system penetration and a wide array of biological activities that may lead to adverse effects. A potential approach for addressing these limitations is the development of synthetic, small molecule, neurotrophin mimetics with favorable profiles of stability, tissue penetration and targeted biological actions. Neurotrophin mimetic strategies include development of agents that act at neurotrophin receptors as agonists, partial agonists, inverse agonists or antagonists to promote, inhibit or modify neurotrophin- related signal transduction. The existence of a two-receptor system for neurotrophins, suggests the possibility that small molecules mimicking p75NTR versus Trk-interacting neurotrophin domains might differentially promote selected neurotrophin functions. Moreover, the principle of differential receptor activation predicts that different mimetics acting at a given neurotrophin receptor might elicit differential signaling patterns and biological effects. For example, prevention of neuronal death in the absence of the neurotrophin effects of upregulation of pain transduction or inflammation might constitute a desired activity profile. Synthesis of active peptide mimetics corresponding to specific neurotrophin domains has established the proof-of-principle that neurotrophin domain mimetics can be created that exhibit antagonist or agonist features and points to the possibility of creating non-peptide, small molecule mimetics with favorable medicinal properties and targeted neurotrophin activities.