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Abstract Details

Mechanism of Action, Preclinical Efficacy, and Safety Evaluation of ACP-711 (SAN711): A Novel GABAA Subunit a3 Selective Modulator
Movement Disorders
P8 - Poster Session 8 (11:45 AM-12:45 PM)
17-012
Evaluate the pharmacology, efficacy, and adverse effects (AEs) of ACP-711 (SAN711) in vitro and in preclinical animal models of essential tremor (ET).
ET is one of the most common neurological diseases, with an unknown exact etiology. Dysfunctional GABA signaling may play a role; however, many GABAergic medications have significant AEs when treating ET. ACP-711 is a novel GABAA receptor (R) subunit α3 selective positive allosteric modulator (PAM) designed to have an improved AE profile compared with other GABAergic drugs.

The efficiency of ACP-711 to modulate GABAAR subtype activity was explored in X. laevis oocytes expressing human GABAARs, with α subunit subtypes 1, 2, 3, or 5. In vivo binding of ACP-711 to mouse forebrain GABAARs was evaluated with injections of 3H-flumazenil, which selectively binds with high affinity to GABAARs, following ACP-711 doses. 

Antitremor properties of ACP-711 were assessed in rats using a harmaline model of ET. Potential AEs associated with GABAAR modulation (sedation and motor coordination) were evaluated in rat models using nonselective GABAA PAM diazepam as a comparator. Sedative effects were tested by monitoring exploratory locomotor activity. Motor coordination was evaluated using a rotating accelerating rod (RotaRod) device.
In X. laevis oocytes, ACP-711 demonstrated potent positive allosteric modulation of GABAAR with EC50s between 85-280 nM and an efficiency selectivity order of α3β2γ2 > α2β2γ2 = α5β2γ2 >> α1β2γ2. ACP-711 inhibited in vivo binding of 3H-flumazenil in the mouse forebrain (estimated ED50, 0.7 mg/kg; corresponds to plasma concentration of 0.32 μM). ACP-711 dose-dependently decreased harmaline-induced tremors in rats, with a minimal effective dose of 1 mg/kg significantly reducing motion power percentage. Effects on activity and motor coordination in doses ≤30 mg/kg were not significantly different from vehicle; diazepam led to significant sedation and motor impairment.
In rodent models, ACP-711 has shown efficacy in treating harmaline-induced tremors with no detectable AEs.
Authors/Disclosures
Robert Hofbauer, PhD
PRESENTER 		Dr. Hofbauer has received personal compensation for serving as an employee of Acadia Pharmaceuticals. Dr. Hofbauer has or had stock in Acadia Pharmaceuticals.
Dipak V. Amrutkar, PhD Dr. Amrutkar has stock in Saniona.
Karin Sandager Nielsen, PhD Dr. Sandager Nielsen has received personal compensation for serving as an employee of Saniona. Dr. Sandager Nielsen has stock in Saniona.
Tino Dyhring, PhD Mr. Dyhring has nothing to disclose.
Thomas A. Jacobsen, Master of Science Mr. Jacobsen has received personal compensation for serving as an employee of Saniona. Mr. Jacobsen has stock in Saniona.
Janus S. Larsen, PhD Mr. Larsen has received personal compensation for serving as an employee of Saniona A/S. Mr. Larsen has stock in Saniona A/S.
Pierandrea Muglia, MD Dr. Muglia has received personal compensation for serving as an employee of Saniona. Dr. Muglia has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Grin therapeutics. Dr. Muglia has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Saniona A/S. Dr. Muglia has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Grin therapeutics. Dr. Muglia has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Saniona. Dr. Muglia has stock in Saniona. Dr. Muglia has stock in Grin therapeutics.
Sanjeev Pathak, MD (Acadia Pharmaceuticals) Dr. Pathak has received personal compensation for serving as an employee of Acadia Pharmaceuticals.
Hank H. Lin, PhD Dr. Lin has received personal compensation for serving as an employee of Acadia Pharmaceuticals.