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 individual receptor subtypes mediate these opposing responses. α1-ARs are the most abundantly expressed adrenoceptors in the CNS, where they serve as stimulatory receptors in postsynaptic cell bodies. Stimulation of α1-ARs in these cells increases the excitatory potential of glutamate and acetylcholine and 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 validating these receptors as genuine targets for treating epilepsy, Parkinson’s, and Alzheimer’s disease difficult.

We have engineered thermostabilised 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.