title: Low molecular weight, non-peptidic agonists of TrkA receptor with NGF-mimetic activity.
abstract: 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 (nerve growth factor)-mimetic properties. MT2, a representative compound, bound to Trk (tropomyosin kinase receptor)A 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 amino-acid residues within TrkA molecule. Like NGF, MT2 increased phosphorylation of extracellular signal-regulated kinase 1/2 and Akt proteins and production of MKP-1 phosphatase (dual specificity phosphatase 1), modulated p38 mitogen-activated protein kinase activation,sustained survival of serum-starved PC12 or RDG cells, and promoted their differentiation. However, the intensity of such responses was heterogenous, as the ability of maintaining survival was equally possessed by NGF and MT2, whereas the induction of differentiation was expressed at definitely lower levels by the mimetic. Analysis of TrkA autophosphorylation patterns induced by MT2 revealed a strong tyrosine (Tyr)490 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.
authors.affiliation: Department of Chemistry 'Ugo Schiff', University of Firenze, Via della Lastruccia 13, Sesto Fiorentino, I-50019 Firenze, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Scarpi
authors.forename: D
authors.initials: D
authors.lastname: Cirelli
authors.forename: C
authors.initials: C
authors.lastname: Matrone
authors.forename: G
authors.initials: G
authors.lastname: Castronovo
authors.forename: P
authors.initials: P
authors.lastname: Rosini
authors.forename: E G
authors.initials: EG
authors.lastname: Occhiato
authors.forename: F
authors.initials: F
authors.lastname: Romano
authors.forename: L
authors.initials: L
authors.lastname: Bartali
authors.forename: A M
authors.initials: AM
authors.lastname: Clemente
authors.forename: G
authors.initials: G
authors.lastname: Bottegoni
authors.forename: A
authors.initials: A
authors.lastname: Cavalli
authors.forename: G
authors.initials: G
authors.lastname: De Chiara
authors.forename: P
authors.initials: P
authors.lastname: Bonini
authors.forename: P
authors.initials: P
authors.lastname: Calissano
authors.forename: A T
authors.initials: AT
authors.lastname: Palamara
authors.forename: E
authors.initials: E
authors.lastname: Garaci
authors.forename: M G
authors.initials: MG
authors.lastname: Torcia
authors.forename: A
authors.initials: A
authors.lastname: Guarna
authors.forename: F
authors.initials: F
authors.lastname: Cozzolino
mesh_terms: D000818:Animals; D001381:Azepines / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008970:Molecular Weight; D041681:NIH 3T3 Cells; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D016716:PC12 Cells; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D020917:Receptor, trkA / Q000819:agonists* / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D001381:Azepines; D011994:Recombinant Proteins; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases