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.
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 D3/D2 receptor antagonist with subnanomolar affinity for the D3 receptor and nanomolar affinity for the D2 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 ED50 (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 D3 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 D3 receptor antagonism coupled to moderate D2 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.
Research Division, Gedeon Richter Plc., Budapest 1475, Hungary. i.gyertyan@richter.hu
István
I
Gyertyán
Katalin
K
Sághy
Judit
J
Laszy
Ottilia
O
Elekes
Rita
R
Kedves
Larisza I
LI
Gémesi
Gabriella
G
Pásztor
Mária
M
Zájer-Balázs
Margit
M
Kapás
Eva
E
Agai Csongor
György
G
Domány
Béla
B
Kiss
Zsolt
Z
Szombathelyi
D000077582:Amisulpride; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D001362:Avoidance Learning / Q000187:drug effects; D001569:Benzodiazepines / Q000494:pharmacology; D001682:Biological Availability; D002375:Catalepsy / Q000139:chemically induced; D003024:Clozapine / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D000077152:Olanzapine; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D013469:Sulpiride / Q000031:analogs & derivatives / Q000494:pharmacology; D014018:Tissue Distribution
D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; C539157:N-(4-(2-(4-(3-cyano-5-trifluoromethylphenyl)piperazin-1-yl)ethyl)cyclohexyl)-3-pyridinesulfonic amide; D011725:Pyridines; D050637:Receptors, Dopamine D3; D013449:Sulfonamides; D001569:Benzodiazepines; D013469:Sulpiride; D000077582:Amisulpride; D003024:Clozapine; D000077152:Olanzapine