Synthesis and Structure-Activity Relationships for Glutamate Transporter Allosteric Modulators.

Excitatory amino acid transporters (EAATs) are essential CNS proteins that regulate glutamate levels. Excess glutamate release and alteration in EAAT expression are associated with several CNS disorders. Previously, we identified positive allosteric modulators (PAM) of EAAT2, the main CNS transporter, and have demonstrated their neuroprotective properties in vitro. Herein, we report on the structure-activity relationships (SAR) for the analogs identified from virtual screening and from our medicinal chemistry campaign. This work identified several selective EAAT2 positive allosteric modulators (PAMs) such as compounds 4 (DA-023) and 40 (NA-014) from a library of analogs inspired by GT949, an early generation compound. This series also provides nonselective EAAT PAMs, EAAT inhibitors, and inactive compounds that may be useful for elucidating the mechanism of EAAT allosteric modulation.

Comparative Bending Strength of Metacarpal Neck Fractures Fixed with Two Types of Intramedullary Screws.

Objectives: Intramedullary (IM) screw fixation of metacarpal fractures is a technique, which has gained in popularity owing to its simplicity, speedy rehabilitation, and good functional outcomes. A new, larger diameter, non-compression screw designed specifically for IM metacarpal fixation was recently introduced which could provide better fracture stability and reduce the risk of hardware failure. Our goal was to evaluate the strength of this screw compared to a first-generation screw. Methods: This mechanical study was designed to compare a 4.5 mm metacarpal headless screw (MCHS) to data from our prior research evaluating a 3.0 mm headless screw (HS). Accordingly, we used identical bone models, testing constructs, equipment, and protocols. A metacarpal neck osteotomy was created in 10 Sawbones models. A 4.5 mm x 50 mm MCHS was inserted retrograde to stabilize the fracture. Flexion bending strength was measured through a cable tension construct on a materials testing machine. Failure mechanism and strength was recorded and compared to data with a 3.0 mm screw construct. Results: Eight models failed by bending of the intramedullary screw. Two models failed by rotation of the metacarpal head. Failure occurred at an average of 539 N (Range 315 - 735 N). The MCHS demonstrated a significantly greater load to failure compared to the previously studied 3.0 mm HS at 215 N (P<0.05). Conclusion: A larger, 4.5 mm metacarpal-specific headless screw is more than twice as strong as a 3.0 mm diameter screw in a metacarpal neck fracture model.