Low molecular weight, non-peptidic agonists of TrkA receptor with NGF-mimetic activity

Exploitation of the biologic activity of neurotrophins is desirable for medical purposes, but their protein nature intrinsically bears adverse pharmacokinetic properties. Here, we report synthesis and biologic characterization of a novel class of low molecular weight, non-peptidic compounds with NGF-mimetic properties. MT2, a representative compound , bound to TrkA chain on NGF-sensitive cells, as well as in cell-free assays, at nanomolar concentrations and induced TrkA autophosphorylation and receptor-mediated internalization. MT2 binding involved at least two aminoacid residues within TrkA molecule. Like NGF, MT2 increased phosphorylation of ERK1/2 and Akt proteins and production of MKP-1 phosphatase, modulated p38 MAPK activation, sustained survival of serum-starved PC12 or RDG cells and promoted their differentiation. However, the intensity of such responses was heterogenous, since the ability of maintaining survival was equally possessed by NGF and MT2, whereas induction of differentiation was expressed at definitely lower levels by the mimetic. Analysis of TrkA autophosphorylation patterns induced by MT2 revealed a strong Tyr490 and a limited Tyr785 and Tyr674/675 activation, findings coherent with the observed functional divarication. Consistently, in an NGF-deprived rat hippocampal neuronal model of Alzheimer Disease, MT2 could correct the biochemical abnormalities and sustain cell survival. Thus, NGF mimetics may reveal interesting investigational tools in neurobiology as well as promising drug candidates.