Drug discovery targeting α1-adrenoceptors (α1-ARs)

α1A- and α1B-adrenoceptors (α1A-AR and α1B-AR) are critical receptors that modulate the nervous system in response to binding adrenaline and noradrenaline, and are currently targeted by hypertension drugs. 

Chronic activity of these receptors can be either damaging or protective to heart and brain function and evidence suggests that these opposing responses are mediated by individual receptor subtypes. α1-ARs are the most abundantly expressed adrenoceptors in the CNS, where they serve as stimulatory receptors in post synaptic cell bodies. Stimulation of α1-ARs in these cells serves to increase the excitatory potential of glutamate and acetylcholine and to prime excitatory synapses. Transgenic mice have been used to demonstrate that α1A-AR and α1B-AR mediate opposing responses to noradrenaline release in the CNS. Whereas α1A-AR activation is antiepileptic, constitutive activation of α1B-AR is pro-epileptic. Similarly, α1A-AR stimulation increases neurogenesis whereas prolonged α1B-AR stimulation is neurodegenerative. The lack of subtype selective ligands makes the validation of these receptors as genuine targets for treating epilepsy, Parkinson’s disease and Alzheimer’s disease difficult. We have engineered thermostabilized α1A-AR and α1B-AR proteins that have enabled us to probe and compare the protein structures of these receptors. Furthermore we are able to conduct novel drug screening campaigns to identify subtype selective α1-AR compounds. In 2015, projects will be offered focused on identifying new α1-AR binding compounds with fragment screening as a starting point for structure based drug design. Students will be trained in techniques including protein structure analysis, computational ligand docking, protein expression and purification, robotic ligand binding assays, cell-based GPCR assays, nuclear magnetic resonance spectroscopy and pharmacological analysis. Ultimately, new α1-AR binding compounds may prove to be promising drug candidates for treating epilepsy and neurodegenerative diseases.

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