Selective,\nIntrinsically Fluorescent Trk Modulating\nProbes

Neurotrophins (NTs) elicit the growth, survival, and\ndifferentiation\nof neurons and other neuroectoderm tissues via activation of Trk receptors.\nHot spots for NT·Trk interactions involve three neurotrophin\nloops. Mimicry of these using “<i>cyclo</i>-organopeptides”\ncomprising loop sequences cyclized onto endocyclic organic fragments\naccounts for a few of the low molecular mass Trk agonists or modulators\nreported so far; the majority are nonpeptidic small molecules accessed\nwithout molecular design and identified in random screens. It has\nproven difficult to verify activities induced by low molecular mass\nsubstances are due to Trk activation (rather than via other receptors),\nenhanced Trk expression, enhanced NT expression, or other pathways.\nConsequently, identification of selective probes for the various Trk\nreceptors (e.g., A, B, and C) has been very challenging. Further,\na key feature of probes for early stage assays is that they should\nbe easily detectable, and none of the compounds reported to date are.\nIn this work, we designed novel <i>cyclo</i>-organopeptide\nderivatives where the organic fragment is a BODIPY fluor and found\nones that selectively, though not specifically, activate TrkA, B,\nor C. One of the assays used to reach this conclusion (binding to\nlive Trk-expressing cells) relied on intrinsic fluorescence in the\ntested materials. Consequently, this work established low molecular\nmass Trk-selective probes exhibiting neuroprotective effects.