Preclinical Pharmacodynamic and Pharmacokinetic Characterisation of HTL A a Selective GPR52 Agonist
By Clíona MacSweeney, Simon Poulter, Nigel Austin, Andy Mead, Alastair Brown, Matt Barnes, Ben Grayson, Nagi Idris, Jo Neill, Steve Watson | May 7, 2020
Clíona MacSweeney, Associate Director, Translational Sciences at Sosei Heptares, recently shared her poster describing the pharmacodynamic and pharmacokinetic characterisation of our novel GPR52 agonist on the Society of Biological Psychiatry 75th Anniversary Meeting website portal. The online portal of posters and presentations can be accessed here by registered members. To view Cliona's poster, please scroll to the bottom of this page.
GPR52 has been proposed as a target for the treatment of positive, negative and cognitive symptoms of schizophrenia. High expression of the receptor on D2 receptor-expressing medium spiny neurons and D1 cortical neurons suggests that a GPR52 agonist will selectively modulate dopaminergic and glutamatergic signalling without causing the adverse effects associated with antipsychotics. The pharmacokinetic properties of HTL-A, a selective GPR52 agonist (pEC50 7.5), were measured in preclinical species and pharmacodynamic effects were explored in the rat subchronic PCP-induced cognitive deficit model. A neurobehavioural (Irwin) test was performed following repeat dosing to evaluate potential adverse nervous system effects.
Reversal learning was tested following HTL-A treatment (1-30 mg/kg, PO) in female Lister Hooded rats previously treated with PCP (2 mg/kg, IP) twice daily for 7 days. Irwin and catalepsy tests were performed in male Wistar rats during 10 days’ treatment at 10-100 mg/kg/d, PO. Further studies were performed to understand the pharmacokinetics and bioavailability in preclinical species.
HTL-A reversed the subchronic PCP-induced reversal learning deficit across a range of doses (p<0.05 vs vehicle at 5-30 mg/kg) and no adverse effects were observed in the Irwin or catalepsy tests. HTL-A demonstrates excellent pharmacokinetic properties across preclinical species, with predicted low clearance and good bioavailability in human.
Overall, these studies support the progression of HTL-A as a safe treatment for cognitive dysfunction in patients with psychotic disorders.