Synthesis and Pharmacological Characterization of 2-(2,6-Dichlorophenyl)-1-((1S,3R)-5-(3-hydroxy-3-methylbutyl)-3-(hydroxymethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (LY3154207), a Potent, Subtype Selective, and Orally Available Positive Allosteric Modulator of the Human Dopamine D1 Receptor.

Clinical development of catechol-based orthosteric agonists of the dopamine D1 receptor has thus far been unsuccessful due to multiple challenges. To address these issues, we identified LY3154207 (3) as a novel, potent, and subtype selective human D1 positive allosteric modulator (PAM) with minimal allosteric agonist activity. Conformational studies showed LY3154207 adopts an unusual boat conformation, and a binding pose with the human D1 receptor was proposed based on this observation. In contrast to orthosteric agonists, LY3154207 showed a distinct pharmacological profile without a bell-shaped dose-response relationship or tachyphylaxis in preclinical models. Identification of a crystalline form of free LY3154207 from the discovery lots was not successful. Instead, a novel cocrystal form with superior solubility was discovered and determined to be suitable for development. This cocrystal form was advanced to clinical development as a potential first-in-class D1 PAM and is now in phase 2 studies for Lewy body dementia.

Powered exoskeleton with palm degrees of freedom for hand rehabilitation.

Robotic rehabilitation is a currently underutilised field with the potential to allow huge cost savings within healthcare. Existing rehabilitation exoskeletons oversimplify the importance of movement of the hand while undertaking everyday tasks. Within this study, an investigation was undertaken to establish the extent to which the degrees of freedom within the palm affect ability to undertake everyday tasks. Using a 5DT data glove, bend sensing resistors and restrictors of palm movement, 20 participants were recruited to complete tasks that required various hand shapes. Collected data was processed and palm arching trends were identified for each grasping task. It was found that the extent of utilizing arches in the palm varied with each exercise, but was extensively employed throughout. An exoskeleton was subsequently designed with consideration of the identified palm shapes. This design included a number of key features that accommodated for a variety of hand sizes, a novel thumb joint and a series of dorsally mounted servos. Initial exoskeleton testing was undertaken by having a participant complete the same exercises while wearing the exoskeleton. The angles formed by the user during this process were then compared to those recorded by 2 other participants who had completed the same tasks without exoskeleton. It was found that the exoskeleton was capable of forming the required arches for completing the tasks, with differences between participants attributed to individual ergonomic differences.