GABA Receptor Agonist Development for Stroke

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain and is important for motor learning. GABA signaling in the motor cortex plays an important role in the development of peri-infarct or use-dependent plasticity after stroke. Several animal studies have found that GABA activity in the peri-infarct cortex increases initially but decreases over time during functional recovery and motor improvement. Changes in GABA function after cerebral ischemia and the protective effects of GABAergic compounds targeting synaptic GABA receptors have been reported. GABA receptor agonists have shown great promise in animal models of stroke with neuroprotective effects, reducing infarct size and improving functional outcomes in animal models of cerebrovascular disease.

Fig. 1. Targeting GABA_C receptors improves post-stroke motor recovery. (van, et al., 2021)

Our GABA Receptor Agonist Development Services

Ace Therapeutics provides comprehensive GABA receptor agonist development services to help clients develop stroke drugs. Our multidisciplinary approach combines expertise in neuroscience, pharmacology, and medicinal chemistry to drive innovation and accelerate the preclinical development of promising compounds.

Development of Compounds Targeting the GABA Receptor

Leveraging our extensive knowledge of GABA receptor subtypes and their role in stroke recovery, we apply rational drug design strategies to develop highly selective and potent GABA receptor agonists. Using computer-aided drug design tools, molecular modeling techniques, and conformational studies, we are able to optimize the chemical structure of compounds to enhance their affinity and potency for specific GABA receptor subtypes.

• Targeting the GABA_A receptor
• Targeting the GABA_C receptor

In Vitro and In Vivo Assessment of GABA Receptor Agonists

We provide in vitro models of ischemic injury, such as oxygen-glucose deprivation in neuronal cultures, for evaluating the ability of GABA agonists to prevent excitotoxicity and apoptosis.

We also provide rodent middle cerebral artery occlusion models to evaluate the effects of GABA agonists on infarct size, neurological outcome, and other stroke-related endpoints. We perform comprehensive ADME (absorption, distribution, metabolism, excretion) analysis and safety pharmacology studies to characterize the drug-like properties of GABA receptor agonists and determine the optimal therapeutic window.

• BBB permeability measurements
• Monitoring the area of cerebral infarction in animals with magnetic resonance imaging (MRI).
• TTC staining of brain slices
• Behavioral testing to assess neurological dysfunction
• Detecting changes in the expression of glial markers, glial fibrillary acidic protein (GFAP) and GAT3 in animals with molecular techniques.
• Measuring extracellular free GABA levels and receptor activity using positron emission tomography (PET) technique.

Ace Therapeutics has specialized teams in medicinal chemistry, pharmacology, and toxicology to support you from early discovery to preclinical studies. For the development of GABA receptor agonists for the treatment of stroke, we are your reliable partner for comprehensive services. If you are interested in our services, please do not hesitate to contact us!

1. van Nieuwenhuijzen, P. S., et al. (2021). Targeting GABAC receptors improves post-stroke motor recovery. Brain Sciences, 11(3), 315.