Design, synthesis, and pharmacological evaluation of phenoxy pyridyl derivatives as dual norepinephrine reuptake inhibitors and 5-HT1A partial agonists.

Preclinical studies suggest that compounds with dual norepinephrine reuptake inhibitor (NRI) and 5-HT(1A) partial agonist properties may provide an important new therapeutic approach to ADHD, depression, and anxiety. Reported herein is the discovery of a novel chemical series with a favorable NRI and 5-HT(1A) partial agonist pharmacological profile as well as excellent selectivity for the norepinephrine transporter over the dopamine transporter.

Dry eyes and corneal sensation after laser in situ keratomileusis with femtosecond laser flap creation Effect of hinge position, hinge angle, and flap thickness.

PURPOSE: To determine whether corneal sensation and dry-eye signs and symptoms after myopic laser in situ keratomileusis (LASIK) surgery with a femtosecond laser are affected by varying hinge position, hinge angle, or flap thickness. SETTING: University-based academic practice, Ann Arbor, Michigan, USA. METHODS: This prospective randomized contralateral-eye study evaluated eyes after bilateral myopic LASIK with a femtosecond laser (IntraLase). Superior and temporal hinge positions, 45-degree and 90-degree hinge angles, and 100 microm and 130 microm corneal flap thicknesses were compared. Postoperative follow-up at 1 week and 1, 3, 6, and 12 months included central Cochet-Bonnet esthesiometry, the Ocular Surface Disease Index questionnaire, a Schirmer test with anesthesia, tear breakup time (TBUT), corneal fluorescein staining, and conjunctival lissamine green staining. RESULTS: The study evaluated 190 consecutive eyes (95 patients). Corneal sensation was reduced at all postoperative visits, with improvement over 12 months (P<.001). There was no difference in corneal sensation between the different hinge positions, angles, or flap thicknesses at any time point. The overall ocular surface disease index score was increased at 1 week, 1 month, and 3 months (P<.0001, P<.0001, and P = .046, respectively). The percentage of patients with a TBUT longer than 10 seconds was significantly lower at 1 week and 1 month (P<.0001). CONCLUSIONS: Dry-eye syndrome after myopic LASIK with a femtosecond laser was mild and improved after 3 months. Corneal flap hinge position, hinge angle, and thickness had no effect on corneal sensation or dry-eye syndrome.

The design and synthesis of human branched-chain amino acid aminotransferase inhibitors for treatment of neurodegenerative diseases.

The inhibition of the cytosolic isoenzyme BCAT that is expressed specifically in neuronal tissue is likely to be useful for the treatment of neurodegenerative and other neurological disorders where glutamatergic mechanisms are implicated. Compound 2 exhibited an IC50 of 0.8 microM in the hBCATc assays; it is an active and selective inhibitor. Inhibitor 2 also blocked calcium influx into neuronal cells following inhibition of glutamate uptake, and demonstrated neuroprotective efficacy in vivo. SAR, pharmacology, and the crystal structure of hBCATc with inhibitor 2 are described.

Neuroimmunophilin ligand V-10,367 is neuroprotective after 24-hour delayed administration in a mouse model of diffuse traumatic brain injury.

The authors present two studies that investigate the biochemical and histologic effects of the nonimmunosuppressive neuroimmunophilin (NIMM) ligand V-10,367 in a mouse model of traumatic brain injury (TBI). In study 1, the authors examined the effect of V-10,367 (50 mg/kg x 2 per day, by mouth) on neurofilament M (NFM) protein levels and on alpha-spectrin breakdown products (SBDPs) when dosed for 2 days, starting 24 hours after TBI and killed on day 3. In study 2, V-10,367 was given for 10 days, starting 24 hours after TBI and the mice killed 6 weeks after TBI, to measure the extent of neurodegeneration (amino CuAg stain). The results in study 1 revealed that V-10,367-treatment significantly increased NFM protein levels in both sham and TBI mice. In addition, V-10,367 attenuated SBDP 150 levels in the cortex, striatum, and hippocampus. The results of study 2 indicated that TBI mice treated with V-10,367 demonstrated significantly less neurodegeneration compared to injured, vehicle-treated mice. In summary, these results suggest that NIMMs may be neuroprotective indirectly through inhibition of calpain-mediated cytoskeletal damage and perhaps via maintenance of neuronal plasticity. In the context of this mouse model of TBI, the therapeutic window for V-10,367's positive effects is at least 24 hours after injury, which, in the case of TBI models, is largely unprecedented for a neuroprotective compound.

Selective release of calpain produced alphalI-spectrin (alpha-fodrin) breakdown products by acute neuronal cell death.

Activation of calpain results in the breakdown of alpha II spectrin (alpha-fodrin), a neuronal cytoskeleton protein, which has previously been detected in various in vitro and in vivo neuronal injury models. In this study, a 150 kDa spectrin breakdown product (SBDP150) was found to be released into the cell-conditioned media from SH-SY5Y cells treated with the calcium channel opener maitotoxin (MTX). SBDP150 release can be readily quantified on immunoblot using an SBDP150-specific polyclonal antibody. Increase of SBDP150 also correlated with cell death in a time-dependent manner. MDL28170, a selective calpain inhibitor, was the only protease inhibitor tested that significantly reduced MTX-induced SBDP150 release. The cell-conditioned media of cerebellar granule neurons challenged with excitotoxins (NMDA and kainate) also exhibited a significant increase of SBDP150 that was attenuated by pretreatment with an NMDA receptor antagonist, R(-)-3-(2-carbopiperazine-4-yl)-propyl-1-phosphonic acid (CPP), and MDL28170. In addition, hypoxic/hypoglycemic challenge of cerebrocortical cultures also resulted in SBDP150 liberation into the media. These results support the theory that an antibody-based detection of SBDP150 in the cell-conditioned media can be utilized to quantify injury to neural cells. Furthermore, SBDP150 may potentially be used as a surrogate biomarker for acute neuronal injury in clinical settings.