The 19 F 19 F nuclear spin-spin coupling constants J FF for a set of eighteen compounds related structurally to 1,8-difluoronaphthalene were measured by 19 F NMR spectroscopy. The FF distances d FF in these compounds were determined by ab initio 3-21G* molecular orbital calculations. Consistent with the lone-pair overlap theory of the origins of through-space 19 F 19 F coupling, an exponential relationship is found between J FF and d FF (regression coefficient r 2 ) 0.991), and a linear relationship is found between J FF and the extent of the overlap interaction between the in-plane fluorine 2p lone-pair orbitals (regression coefficient r 2 ) 0.993). The magnitudes of these lone-pair interactions were estimated from molecular orbital energies obtained by ab initio 6-31G* calculations for a model consisting of a pair of HF molecules separated by various distances.
Background: The vacuolar protein sorting 35 (VPS35) is a major component of the retromer complex system, an ubiquitous multiprotein assembly responsible for sorting and trafficking protein cargos out of the endosomes. VPS35 can regulate APP metabolism and Aβ formation, and its levels are reduced in Alzheimer's disease (AD) brains. We and others demonstrated that VPS35 genetic manipulation modulates the phenotype of mouse models of AD. However, the translational value of this observation remains to be investigated. Methods: Triple transgenic mice were randomized to receive a pharmacological chaperone, which stabilizes the retromer complex, and the effect on their AD-like phenotype assessed. Results: Compared with controls, treated mice had a significant improvement in learning and memory, an elevation of VPS35 levels, and improved synaptic integrity. Additionally, the same animals had a significant decrease in Aβ levels and deposition, reduced tau phosphorylation and less astrocytes activation. Conclusions: Our study demonstrates that the enhancement of retromer function by pharmacological chaperones is a potentially novel and viable therapy against AD.
Cocaine use disorder (CUD) currently lacks FDA-approved treatments. In rodents, the glutamate transporter-1 (GLT-1) is downregulated in the nucleus accumbens following cocaine self-administration and increasing the expression and function of GLT-1 reduces the reinstatement of cocaine-seeking. The beta-lactam antibiotic ceftriaxone upregulates GLT-1 and attenuates cue-and cocaine-induced cocaine seeking without affecting motivation for natural rewards. While ceftriaxone shows promise for treating CUD, it possesses characteristics that limit successful translation from bench to bedside, including poor brain penetration, a lack of oral bioavailability and a risk of bacterial resistance when used chronically. Thus, we aimed to develop novel molecules that retained the GLT-1 enhancing effects of ceftriaxone but displayed superior drug-like properties. Here we describe a new monocyclic beta-lactam, MC-100093, as a potent up-regulator of GLT-1 that is orally bioavailable and devoid of antimicrobial properties.MC-100093 was synthesized and tested in vitro and in vivo to determine physiochemical, pharmacokinetic and pharmacodynamic properties. Next, adult male rats underwent cocaine self-administration and extinction training. During extinction training, rats received one of four doses of MC-100093 for 6-8 days prior to a single cue-primed reinstatement test. Separate cohorts of rats were used to assess nucleus accumbens GLT-1 expression and MC-100093 effects on sucrose self-administration. We found that 50 mg/kg MC-100093 attenuated cueprimed reinstatement of cocaine-seeking while upregulating GLT-1 expression in the nucleus accumbens core. This dose did not produce sedation, nor did it decrease sucrose consumption or body weight. Thus, MC-100093 represents a potential treatment to reduce cocaine relapse.
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