Publications by authors named "D Aharony"
Herein, we describe the discovery of inhibitors of norepinephrine (NET) and dopamine (DAT) transporters with reduced activity relative to serotonin transporters (SERT). Two compounds, 8b and 21a, along with nomifensine were tested in a rodent receptor occupancy study and demonstrated dose-dependent displacement of radiolabeled NET and DAT ligands. These compounds were efficacious in a rat forced swim assay (model of depression) and also had activity in rat spontaneous locomotion assay.
View Article and Find Full Text PDFThe peptide corticotropin-releasing factor (CRF) binds to the CRF₁ receptor via a two-domain mechanism such that the extracellular domain (ECD) of the receptor captures the CRF's C-terminus to facilitate the binding of CRF's N-terminus to the juxta-membrane or "J"-site. Known small molecule antagonists bind to the J-site while known CRF₁ receptor peptide radioligands bind to both sites. We report here the in vitro binding properties of the first radioligand that binds exclusively to the ECD of the CRF₁ receptor.
View Article and Find Full Text PDF8-Amino-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline maleate (nomifensine), an antidepressant drug, was withdrawn from the market because of increased incidence of hemolytic anemia, as well as kidney and liver toxicity. Although the nature of the potentially reactive metabolites formed after nomifensine metabolism remains unknown and no glutathione (GSH) adducts of these nomifensine reactive metabolites have been reported, bioactivation has been postulated as a potential mechanism for the toxicity of nomifensine. This study was conducted to probe the potential bioactivation pathways of nomifensine in human and animal hepatocytes and in liver microsomes using GSH as a trapping agent.
View Article and Find Full Text PDFArticle Synopsis
- - Fragment-based lead generation successfully identified a new series of cyclic amidine inhibitors for beta-secretase (BACE-1), starting with initial compounds that showed millimolar activity through NMR screening.
- - Efforts to improve these fragments involved structure-guided techniques using X-ray crystallography and potency testing, resulting in the development of stronger micromolar inhibitors.
- - Further optimization led to the discovery of dihydroisocytosines, achieving submicromolar potency with Compound 29 being the most promising candidate with an IC50 of 80 nM for future research.
Article Synopsis
- Fragment-based lead discovery has been effectively used to target the enzyme BACE-1, which is an aspartyl protease important in various biological processes.
- Initial fragment hits featured an aminopyridine motif that binds to key catalytic aspartic acid residues in the enzyme's active site.
- Through structure-based design, low micromolar lead compounds have been developed, with compounds 4 and 6c showing IC50 values of around 25 microM, and optimized compound 8a achieving a significantly lower IC50 of 690 nM.