Development of Endothelin Receptor Agonists for Stroke

The endothelin (ET) family comprises three isoforms, ET-1, ET-2, and ET-3. ET-1 is a key regulator of vascular function and blood flow in several organ systems, including the central nervous system (CNS), by acting two receptor subtypes: ETA and ET_B. ETA receptors, predominantly found on vascular smooth muscle cells, mediate vasoconstriction upon activation. In contrast, ET_B receptors, primarily found on endothelial cells, promote vasodilation by stimulating the release of nitric oxide. ET_B receptor agonists have been identified as a potential therapeutic approach for the treatment of ischemic stroke, due to their multifaceted effects as angiogenesis-modulating agents, antioxidants, apoptosis inhibitors, and neurogenesis stimulants.

Fig. 1. The standard signaling pathway of Endothelin-1 (ET-1). Fig. 1 The canonical pathway of ET-1. (Enevoldsen, et al., 2020)

Our Endothelin Receptor Agonist Development Services

As a preclinical contract research organization specializing in stroke, Ace Therapeutics is committed to helping clients develop endothelin receptor agonists, with a particular focus on selective ET_B receptor agonists. Our expertise spans the entire drug development process, from target validation to preclinical testing, ensuring that our clients receive reliable solutions tailored to their needs.

Services	Service Details
Target identification and validation	Identify and validate specific ET_B receptors involved in stroke pathology using omics technologies. Predict agonist-receptor interactions to guide the design of high-affinity ligands through molecular docking and dynamics simulations.
High-throughput screening (HTS) of endothelin receptor agonists	Provide comprehensive small molecule and peptide libraries for screening of ET_B receptor agonists. Assess the activity and selectivity of ET_B receptor agonists.
Medicinal chemistry and optimization	Provide iterative structure-activity relationship (SAR) analyses to optimize lead compounds and improve potency, selectivity, and pharmacokinetic properties. Provide in vitro and in vivo ADMET studies to analyze the pharmacokinetics and safety of drug candidates.
Preclinical evaluation	Evaluate the effects of ET_B receptor agonists during middle cerebral artery occlusion on motor function and coordination. Evaluate the effects of ET_B receptor agonists on infarct volume in animal models of middle cerebral artery occlusion. Determine the effects of ET_B receptor agonists during middle cerebral artery occlusion on oxidative stress parameters, including malondialdehyde, reduced glutathione and superoxide dismutase levels in the brain. Determine the effects of ischemia on the regulation of ET receptor levels in the brain by Western blot analysis.

Ace Therapeutics is at the forefront of advancing stroke therapies through the innovative development of novel ET_B receptor agonists. By partnering with us, clients gain access to a dedicated team of scientists, state-of-the-art equipment, and detailed laboratory records to accelerate their stroke drug development programs. If you are interested in our services, please contact us for more information.

Reference

Enevoldsen, F. C., et al. (2020). Endothelin receptor antagonists: status quo and future perspectives for targeted therapy. Journal of clinical medicine, 9(3), 824.

All of our services are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.