Neuropharmacology – Saad Hannan

Neuropharmacology

To achieve the goal of identifying new drug targets for neurological diseases requires a sound understanding of pharmacological properties of therapeutic agents.

Using electrophysiology along with fast application systems I probe pharmacology of therapeutic agents (eg – drugs, proteins and biologics such as nanobodies). We have characterised the neuropharmacological profiles of multiple agents and discovered multiple neurodevelopmental disorders drug targets.

Explore the following pages to gain insights into our efforts in neuropharmacology and drug discovery.

Inhibitory neurosteroids as a therapeutic strategy for spontaneously active GABA_A receptor epilepsy

In genetic epilepsies caused by spontaneously active GABA_A receptor variants, we have corrected dendritic spine defects using a naturally occurring inhibitory neurosteroid called pregnenolone sulphate

Inhibitory neurosteroids

Positive allosteric modulators of GABA_Breceptors as a therapeutic option for genetic epilepsies

In GABA_B receptor variant seizures, we reversed presynaptic hyperexcitability by GABA_B receptor positive allosteric modulation, showcasing the potential of allosteric modulators for treatment

GABA_B postive allosteric modulators I

The most widely used GABA_B receptor positive allosteric modulator is a more potent modulator of GABA_A receptors

CGP7930, the first GABA_B receptor positive allosteric modulator reported in literature has been used by over 50 studies. Worryingly, we show that CGP7930 is a potent modulator of GABA_A receptors and also K⁺ channels

Relative strengths of commercially available GABA_B receptor PAMs and pitfalls of their use

The three commercially available GABA_Breceptor positive allosteric modulators (CGP7930, GS39783 and rac-BHFF) have been used widely in animals and in vitro. Click here to learn about their relative strengths in electrophysiological assays and potential pitfalls associated with their use

GABA_B postive allosteric modulators II

The nicotinic acetylcholine receptor antagonist α-bungarotoxin in also an antagonist of GABA_A receptors

α-bungarotoxin, produced by the branded krait, is a widely used nicotinic acetylcholine receptor (nAchR) antagonist. We have shown that this protein can also inhibit GABA_A receptors that are a part of the same Cys-loop family of pentameric ligand-gated ion channels as nAchRs

α-bungarotoxin

Specific nanobodies are more potent positive allosteric modulators of GABA_A receptors than the widely used diazepam

In collaboration with Dr Paul Miller (University of Cambridge) and Professor Radu Aricescu (Lab of Molecular Biology, Cambridge UK) we have shown that specific nanobodies are more potent positive allosteric modulators of GABA_A receptors in brain slices compared to the widely used (and abused) diazepam