Optimization of New Drugs for the Treatment of Essential Tremor - PROJECT SUMMARY Essential tremor (ET) is one of the most common neurological diseases, with an estimated seven million affected persons in the USA. The disease is chronic and progressive. It is poorly served by currently available medications that initially were approved for other indications. Here, we describe a new approach to discovering novel compounds tailored explicitly toward the hypothesized underlying causes of ET. Although the etiology and pathophysiology of ET are not yet fully understood, human data strongly implicates: i) endogenous β-carbolines (e.g., harmane) in the etiology of ET and (ii) a disturbance of the GABAergic system in the pathophysiology of ET. Harmane is a negative allosteric modulator (NAM) that reduces the maximal functional response elicited by GABA and binds at an allosteric site different from the benzodiazepine site. Indeed, exogenous administration of harmine causes tremors in humans. We have identified a mechanistically unique strategy to treat ET and restore GABAA functional tone to a normal state while avoiding the side effects typically associated with excessive GABAA potentiation. Our preliminary studies identified both (i) GABAA precision PAMs and (ii) dual GABAA precision PAM/β2-adrenergic receptor antagonists that were efficacious in the harmaline model of ET without sedation. With optimized PK and brain exposure, we believe that a GABAA precision PAM will restore proper motor function in brain regions affected in ET without the side effects of excessive GABAA potentiation (e.g., sedation). Our Aims are as follows: AIM 1: Medicinal chemistry optimization and in vitro characterization of novel β-carboline GABAA PAMs. ZK-95962 was a promising GABAA partial agonist, but high clearance, poor oral bioavailability, and sedation halted its clinical development. We propose that (i) the cause of the poor PK of ZK-95962 (e.g., ester hydrolysis) can be successfully addressed, and (ii) its excessive GABA potentiation can be fine-tuned by appropriate substitution. Therefore, this aim aims to identify novel β-carboline GABAA precision PAMs and significantly improve these compounds' metabolic stability and PK properties. AIM 2: In vivo evaluation of lead molecules in the harmaline model of ET. Three GABAA precision PAMs and three dual-acting compounds (e.g., β2-ADR antagonist/GABA precision PAM) that satisfy the stringent criteria defined in Table 3 will be scaled up for evaluation in the harmaline model. Efficacious compounds will be tested in three models (righting reflex, rotarod, and SLA) that can detect different indicators of sedation. For a compound to advance, it must in all three safety models, demonstrate a NOAEL ≥30X above its ED50 in the harmaline ET efficacy model. Compounds with a NOAEL ≥100X will be preferred. A positive result will provide mechanistic support for the proposition that a precision GABAA PAM can eliminate tremors in the harmaline model of ET without sedative side effects and the identification of compounds suitable for advancement into preclinical safety testing.
