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P0279 - RGH-188, a d3/d2 dopamine receptor antagonist/partial agonist atypical antipsychotic candidate

Published online by Cambridge University Press:  16 April 2020

I. Laszlovszky
Affiliation:
Gedeon Richter Plc., Medical Division, Budapest, Hungary
B. Kiss
Affiliation:
Gedeon Richter Plc., Pharmacological and Drug Safety Research, Budapest, Hungary
I. Gyertyan
Affiliation:
Gedeon Richter Plc., Pharmacological and Drug Safety Research, Budapest, Hungary
G. Pasztor Meszaros
Affiliation:
Gedeon Richter Plc., Pharmacological and Drug Safety Research, Budapest, Hungary
N. Seneca
Affiliation:
Karolinska Institute, Department of Clinical Neuroscience, Psychiatry Section, Stockholm, Sweden
E. Schmidt
Affiliation:
Gedeon Richter Plc., Pharmacological and Drug Safety Research, Budapest, Hungary
Z.S. Nemethy
Affiliation:
Gedeon Richter Plc., Pharmacological and Drug Safety Research, Budapest, Hungary
G.Y. Bugovics
Affiliation:
Gedeon Richter Plc., Pharmacological and Drug Safety Research, Budapest, Hungary
K. Saghy
Affiliation:
Gedeon Richter Plc., Pharmacological and Drug Safety Research, Budapest, Hungary
J. Laszy
Affiliation:
Gedeon Richter Plc., Pharmacological and Drug Safety Research, Budapest, Hungary
M. Kapas
Affiliation:
Gedeon Richter Plc., Pharmacological and Drug Safety Research, Budapest, Hungary
G.Y. Nemeth
Affiliation:
Gedeon Richter Plc., Medical Division, Budapest, Hungary
Z.S. Szombathelyi
Affiliation:
Gedeon Richter Plc., Pharmacological and Drug Safety Research, Budapest, Hungary
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Abstract

Objectives:

RGH-188 is an orally active, potent dopamine D3/D2 receptor antagonist/partial agonist atypical antipsychotic for the treatment of schizophrenia and bipolar mania.

Results:

RGH-188 displayed high affinity to human D3 receptors (Ki: 0.085 nM) and approximately six- and thirty-times less affinity to human D2, and 5-HT1A receptors. In various in vitro and in vivo assays RGH-188 behaved either as an antagonist or as a partial agonist on dopamine D3 and D2 receptors.

RGH-188 displayed potent antipsychotic activity (0.1-0.8 mg/kg) in rodent models such as apomorphine-induced climbing, amphetamine- and phencyclidine-induced hypermotility, conditioned avoidance response. It significantly improved the learning performance of rats (0.02-0.2 mg/kg) impaired by scopolamine in a water-labyrinth learning paradigm. RGH-188 showed no EPS liability as it produced no catalepsy up to 100-fold therapeutic range.

In a nonhuman primate positron emission tomography (PET) study using 11C-raclopride RGH-188 occupied striatal D2/D3 receptors in a dose dependent and saturable manner with an ED50 of 7 μg/kg iv. In healthy male subjects multiple administration of 1 mg RGH-188 resulted in over 70% D2/D3 receptor occupancy and the displacement showed correlation with RGH-188 and metabolites plasma levels.

After single administration to healthy volunteers, Tmax for RGH-188 was 3-4 hours and the terminal disposition half-life was 5-6 days. Over the dose range of 0.5-2.5 mg AUC of the parent drug was approximately dose-proportional. Systemic exposure to the pharmacologically active metabolites, desmethyl- and didesmethyl-RGH-188 was 20-30% and 50-200% of that to the parent, respectively.

Type
Poster Session I: Neuroleptics and Antipsychotics
Copyright
Copyright © European Psychiatric Association 2008

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