Trends in Pharmacological Sciences
ReviewDevelopment of pharmacological agents for targeting neurotrophins and their receptors
Section snippets
Neurotrophin receptors
Two types of neurotrophin transmembrane receptors are known: (1) a receptor termed p75, which is common to all neurotrophins and is bound with relatively low affinity, and (2) a family of neurotrophin receptor tyrosine kinases trkA, trkB and trkC. The trk receptors have relatively higher affinity for neurotrophins and are more selective for the different neurotrophins. For example, NGF binds to trkA, BDNF and NT4/5 bind to trkB, and NT3 binds to trkC. NT3 is more promiscuous than the other
Inhibitors of neurotrophins in pain
Several pharmacological approaches to the development of agents that influence neurotrophin function have been attempted. Antibodies to neurotrophins have been used in vivo as blocking agents or antagonists to inhibit certain types of pain in which neurotrophins are involved. However, an alternative to antibodies is the use of peptides that contain the extracellular domain (ECD) of receptors as growth factor scavengers. The ECD of the trkA receptor acts as a decoy or ‘pseudoreceptor’ and binds
Small-molecule-based pharmacological agents
Because of the problems with protein-based therapies, alternative approaches are necessary. Two general approaches will be discussed. One approach affords agents with intrinsic neurotrophic activity; importantly, these ligands retain receptor specificity and affect only target cells that express the appropriate trk or p75 receptor. The design of small-molecule neurotrophin mimetics and mimetics of antibodies for neurotrophin receptors, and the screening of natural products or chemical libraries
Neurotrophin and antibody mimetics as agonists and antagonists
Ligand mimicry18 is a process by which a large polypeptide ligand is reduced to smaller functional units that contain sites of the protein that bind to and activate (or block) specific receptors. Thus, well designed, small-molecule analogs mimic the binding of the original ligand and interact specifically with the appropriate receptors and can act as receptor modulators, biological response modifiers, antagonists or partial agonists15, 16. Mimicry is possible because many protein–protein
High-throughput screening of receptor ligands
High-throughput screens of biological (e.g. phage display and peptide display)15, peptidic26 or chemical libraries (e.g. natural products or combinatorial chemistry)27 are possible sources to identify ligands of neurotrophins or their receptors. Generally, these automated screens rely on either the inhibition of radiolabeled neurotrophin binding to a purified receptor or on the inhibition of the biological signal of a receptor in response to a neurotrophin.
Development of biological response
Induced endogenous production of neurotrophins
Vitamin D induces the production of neurotrophins and other factors. Certain vitamin D analogs have the added advantage of not causing undesirable effects on Ca2+ metabolism. The development of local inducers of neurotrophin synthesis is viewed with optimism for the potential therapy of neurodegenerative conditions such as AD and Parkinson’s disease.
Analogs of hypoxanthine and other purines induce local production of mRNA for NGF and NT3. Activity is notable in the hippocampus and cortex, areas
Molecules with neurotrophic-like activity
Staurosporine-like alkaloids can either stimulate or antagonize trkA receptor signals in a dose-dependent fashion. As expected, biological outcomes are related to drug concentration. However, unexpectedly, the mechanism of action of the alkaloids differs from one analog to another. For example, one analog inhibits a pro-apoptotic kinase upstream of the JUN kinase30, whereas another analog potentiates trk receptor activation by sub-optimal NT3 concentrations31. In addition to the intriguing
Concluding remarks
Several conditions, such as neurodegeneration, neuropathies, pain and cancer, are thought to involve a disruption in the regulation of neurotrophins or their receptors. Therefore, targeting of neurotrophin-mediated signaling pathways provides a rationale for therapeutic intervention. It is very likely that the clinical milieu and the marketplace will not support further large-scale attempts to use neurotrophins as therapeutic agents. Therefore, small, non-peptidic compounds that possess either
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