A unique target for a comprehensive therapy of Alzheimer’s disease: concomitant activation of SIGMA1/M1 muscarinic receptors

Nerve growth factor (NGF) is critical for the proliferation, differentiation, and survival of neurons through its binding to the p75NTR and TrkA receptors. Dysregulation of NGF has been implicated in several pathologies, including neurodegeneration (i.e., Parkinson's and Alzheimer's diseases) and both inflammatory and neuropathic pain states. Therefore, small molecule inhibitors that block NGF–receptor interactions have significant therapeutic potential. Small molecule antagonists ALE-0540, PD90780, Ro 08-2750, and PQC 083 have all been reported to inhibit NGF from binding the TrkA receptor. Interestingly, the characterization of the ability of these molecules to block NGF–p75NTR interactions has not been performed. In addition, the inhibitory action of these molecules has never been evaluated using surface plasmon resonance (SPR) spectroscopy, which has been proven to be highly useful in drug discovery applications. In the current study, we used SPR biosensors to characterize the binding of NGF to the p75NTR receptor in addition to characterizing the inhibitory potential of the known NGF antagonists. The results of this study provide the first evaluation of the ability of these compounds to block NGF binding to p75NTR receptor. In addition, only PD90780 was effective at inhibiting the interaction of NGF with p75NTR, suggesting receptor selectivity between known NGF inhibitors.