Mechanism of Action, Preclinical Efficacy, and Safety Evaluation of ACP-711 (SAN711): A Novel GABAA Subunit α3 Selective Modulator
Dipak V. Amrutkar1, Karin Sandager-Nielsen1, Tino Dyhring1, Thomas Amos Jacobsen1, Janus S. Larsen1, Pierandrea Muglia1, Sanjeev Pathak2, Hank Lin2, Robert Hofbauer2
1Saniona A/S, 2Acadia Pharmaceuticals, Inc.
Objective:
Evaluate the pharmacology, efficacy, and adverse effects (AEs) of ACP-711 (SAN711) in vitro and in preclinical animal models of essential tremor (ET).
Background:
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.
Design/Methods:
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.
Results:
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.
Conclusions:
In rodent models, ACP-711 has shown efficacy in treating harmaline-induced tremors with no detectable AEs.
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