CHISHIKI

Drug Discovery

Modulation of dopaminergic and glutamatergic function by GPR52 agonist supports therapeutic utility as novel treatment for positive symptoms and cognitive dysfunction in psychotic disorders including schizopherenia

By Cliona MacSweeney, Steve Watson, Alastair Brown, Geor Bakker, Richard Mould, Matt Barnes, Pradeep Nathan | Dec 12, 2019

About the Conference

American College of Neuropsychopharmacology (ACNP) 2019

8-11 December 2019

Florida, US

Conference Website 

 

Summary          

Cliona MacSweeney, Associate Director, Translational Sciences, attended American College of Neuropsychopharmacology (ACNP) 2019 in Florida, US on 8-11 December and presented on Modulation of dopaminergic and glutamatergic function by GPR52 agonist supports therapeutic utility as novel treatment for psychosis.

 

Poster Abstract

Modulation of dopaminergic and glutamatergic function by GPR52 agonist supports therapeutic utility as novel treatment for positive symptoms and cognitive dysfunction in psychotic disorders including schizophrenia

 

Clíona MacSweeney1, Steve Watson1, Alastair Brown1, Geor Bakker1, Richard Mould2,

Matt Barnes1, Ben Grayson3, Nagi Idris3, Jo Neill3, Pradeep Nathan1,4

  1. Sosei Heptares, Cambridge, UK
  2. MSD, London, UK
  3. Division of Pharmacy, University of Manchester, UK
  4. Department of Psychiatry, University of Cambridge, UK

 

Background

GPR52 is a Gs coupled orphan receptor which is highly expressed in the striatum, exclusively on medium spiny neurons expressing dopamine D2 receptors, and on cortical pyramidal neurons expressing dopamine D1 receptors. Based on its localization and functional coupling, GPR52 may play a role in the modulation of fronto-striatal and limbic dopamine in neuropsychiatric disorders. GPR52 agonists are thought to be particularly relevant to the treatment of psychotic disorders, including schizophrenia, where they are hypothesized to improve cognition and negative symptoms indirectly by potentiating D1 signalling, but alleviate positive symptoms through inhibition of D2-mediated signalling in the striatum.

Biodistribution studies of GPR52 mRNA in mice suggest that the receptor may also be co-localised with cholinergic and glutamatergic systems. GPR52’s potential role in the modulation of cholinergic and glutamatergic signalling has not been fully explored to date but is also highly relevant to the treatment of neuropsychiatric disorders. Currently, no effective therapeutic strategies exist to treat cognitive and negative symptoms in neuropsychiatric disorders, and existing atypical antipsychotics are associated with adverse effects. Given the important implications of early published findings, the current study sought firstly to replicate initial studies performed with the GPR52 agonist, 4-(3-(3-fluoro-5-(trifluoromethyl)-benzyl)-5-methyl-1H-1,2,4-triazol-1-yl)-2-methylbenzamide (FTBMT), where positive effects were noted in mouse psychostimulant-induced hyperlocomotion assays. The potential for tachyphylaxis was also investigated using a subchronic dosing regimen. Efficacy of Sosei Heptares compound, HTL-A, a selective GPR52 agonist (pEC50 7.5) with excellent pharmacokinetic properties across preclinical species, was explored. The compound was investigated in psychostimulant-induced hyperlocomotion and a subchronic PCP-induced deficit in the reversal learning task (for cognitive flexibility/executive function) associated with glutamatergic dysfunction.

 

Methods

FTBMT and HTL-A were tested in d-amphetamine induced hyperlocomotor studies. Male Sprague-Dawley rats received FTBMT or HTL-A at 1, 3 and 10 mg/kg, PO, 1 hour prior to injection of d-amphetamine (0.5 mg/kg, SC). Locomotor activity was recorded for 2 hours following injection of the psychostimulant. Tachyphylaxis was investigated in a separate experiment by comparing d-amphetamine-stimulated locomotor activity responses following acute versus 10 days’ treatment with FTBMT (10 mg/kg, PO). Vehicle control groups were included. Reversal learning was performed in adult female Lister Hooded rats treated with PCP (2 mg/kg) or saline IP twice daily for 7 days, followed by >7 days washout. Rats were treated with HTL-A (1, 5 or 15 mg/kg, PO) and 2 hours later underwent the reversal learning task.

 

Results

FTBMT dose-dependently decreased the hyperlocomotor response to d-amphetamine (p<0.05 vs vehicle control at 10 mg/kg). No tachyphylaxis was observed following 10 days of treatment with FTBMT. HTL-A dose-dependently reduced the d-amphetamine hyperlocomotor response (p<0.05 vs vehicle control at 10 mg/kg) and dose-dependently reversed the subchronic PCP-induced deficit in reversal learning (p<0.05 vs vehicle control at 5 and 15 mg/kg).

 

Conclusion

The data confirm previous published effects of FTBMT and demonstrate efficacy of the novel GPR52 agonist, HTL-A, on psychostimulant-induced hyperlocomotor responses, thus further supporting GPR52 as a target in the modulation of striatal hyperdopaminergic pathways. The efficacy of FTBMT in attenuating d-amphetamine hyperlocomotion after both acute and subchronic treatment indicated an absence of tachyphylaxis. HTL-A reversed the PCP-induced deficit in the reversal learning task which measures cognitive flexibility, suggesting GPR52 modulation of glutamatergic dysfunction. These studies provide further support for GPR52 as a promising target for the development of a novel class of antipsychotic with the potential to also improve cognitive/executive dysfunction in patients with psychotic disorders, including schizophrenia.

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