Subnanomolar dopamine D3 receptor antagonism coupled to moderate D2 affinity results in favourable antipsychotic-like activity in rodent models: II. behavioural characterisation of RG-15

• Published in: Naunyn-Schmiedeberg's archives of pharmacology Vol. 378; no. 5; pp. 529 - 539
• Main Authors: Gyertyán, István, Sághy, Katalin, Laszy, Judit, Elekes, Ottilia, Kedves, Rita, Gémesi, Larisza I., Pásztor, Gabriella, Zájer-Balázs, Mária, Kapás, Margit, Ágai Csongor, Éva, Domány, György, Kiss, Béla, Szombathelyi, Zsolt
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.11.2008
• Subjects: Animals; Antipsychotic Agents - administration & dosage; Antipsychotic Agents - pharmacokinetics; Antipsychotic Agents - toxicity; Avoidance Learning - drug effects; Benzodiazepines - pharmacology; Biological Availability; Biomedical and Life Sciences; Biomedicine; Catalepsy - chemically induced; Clozapine - pharmacology; Dopamine Antagonists - administration & dosage; Dopamine Antagonists - pharmacokinetics; Dopamine Antagonists - toxicity; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Male; Motor Activity - drug effects; Neurosciences; Original Article; Pharmacology/Toxicology; Pyridines - administration & dosage; Pyridines - pharmacokinetics; Pyridines - toxicity; Rats; Rats, Wistar; Receptors, Dopamine D3 - antagonists & inhibitors; Sulfonamides - administration & dosage; Sulfonamides - pharmacokinetics; Sulfonamides - toxicity; Sulpiride - analogs & derivatives; Sulpiride - pharmacology; Tissue Distribution; Lack of catalepsy; RG-15; Schizophrenia; Antipsychotic; Dopamine D; receptor antagonist; Cognitive improvement
• DOI: 10.1007/s00210-008-0311-x
• ISSN: 0028-1298

RG-15 ( trans -N-{4-[2-[4-(3-cyano-5-trifluoromethyl -phenyl) –piperazine –1 -yl] -ethyl] -cyclohexyl} -3 –pyridinesulfonic amide dihydro-chloride), is a highly selective dopamine D 3 /D 2 receptor antagonist with subnanomolar affinity for the D 3 receptor and nanomolar affinity for the D 2 receptor. We found that RG-15 showed a good oral bioavailability (54%) and high brain levels (approx. 900 ng/g) in rats and demonstrated antipsychotic efficacy in amphetamine-induced hyperactivity and conditioned avoidance response tests in rats, yielding ED 50 (median effective dose) values of 8.6 and 12 mg/kg orally, respectively. At six- to eightfold higher doses, RG-15 blocked spontaneous motor activity, while a 30 mg/kg dose of the compound caused an increase in the home-cage motility of rats. The drug did not produce catalepsy up to 160 mg/kg oral dose; moreover, it inhibited haloperidol-induced catalepsy in the range 15–60 mg/kg. RG-15 (10 mg/kg orally) restored the impaired learning performance of scopolamine- or diazepam-treated rats in a water-labyrinth paradigm. It is assumed that the motor activating, anticataleptic and cognitive-enhancing properties of RG-15 result from its potent D 3 antagonism. In this regard, RG 15 clearly differs from other antipsychotics. Olanzapine, clozapine and amisulpride all showed efficacy against amphetamine-induced hyperactivity and on conditioned avoidance, but compared to RG-15, they proved to be more cataleptogenic and depressed or did not change the home-cage activity of animals. Olanzapine was also inactive in the learning paradigm. Our results suggest that subnanomolar dopamine D 3 receptor antagonism coupled to moderate D 2 affinity may result in an antipsychotic profile characterised by a lack of extrapyramidal side effects and secondary negative symptoms with simultaneous efficacy on positive and cognitive symptoms of schizophrenia.