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

Abstract

RG-15 (trans-N-[4-[2-[4-(3-cyano-5-trifluoromethyl-phenyl)-piperazine-1-yl]-ethyl]-cyclohexyl]-3-pyridinesulfonic amide dihydrochloride) displayed subnanomolar affinity to human and rat dopamine D3 receptors (pKi 10.49 and 9.42, respectively) and nanomolar affinity to human and rat D2 receptors (pKi 8.23 and 7.62, respectively). No apparent interactions were found with the other 44 receptors and four channel sites tested in this study. RG-15 inhibited dopamine-stimulated [35S]GTPgammaS binding in membranes from rat striatum, in murine A9 cells expressing human D2L receptors and in CHO cells expressing human D3 receptors (IC50 values were 21.2, 36.7 and 7.2 nM, respectively). In these tests RG-15 showed the highest affinity toward D3 receptors when compared to amisulpride, haloperidol and SB-277011. RG-15, similar to haloperidol and amisulpride, dose-dependently inhibited in vivo [3H]raclopride binding in mouse striatum, enhanced dopamine turnover and synthesis rate in mouse and rat striatum and olfactory tubercle. SB-277011 did not change [3H]raclopride binding in mouse striatum nor biosynthesis or turnover rates in either region in mice or rats. RG-15 and haloperidol, but not SB-277011, antagonised dopamine synthesis inhibition induced by the D3/D2 full agonist 7-OH-DPAT in GBL-treated mice. RG-15, but not SB-277011, elevated plasma prolactin levels. In vitro receptor binding and functional experiments demonstrated that RG-15 had an antagonist profile on both D3 and D2 receptors. with high selectivity for dopamine D3 receptors over D2 receptors. However, in vivo, its neurochemical actions were similar to those of D2 receptor antagonists. Neurochemical comparison of RG-15 with antagonists having a different affinity and selectivity toward D3 and D2 receptors indicate that D3 receptors have little, if any, role in the control of presynaptic dopamine biosynthesis/release in dopaminergic terminal regions.

Cariprazine, a new, orally active dopamine D2/3receptor partial agonist for the treatment of schizophrenia, bipolar mania and depression

“…Previous investigations indicated that D 2 antagonism was required for antipsychotic efficacy, but that D 3 receptor antagonism might impart beneficial effects on cognition, while attenuating the EPS. It was hypothesized that the conjunction of subnanomolar D 3 receptor antagonism together with nanomolar D 2 receptor antagonism should therefore yield an antipsychotic compound with a superior side effect profile [28,29].…”

Cariprazine (RGH-188), a Dopamine D3 Receptor-Preferring, D3/D2 Dopamine Receptor Antagonist–Partial Agonist Antipsychotic Candidate: In Vitro and Neurochemical Profile

“…Dopamine, 3,4-dihydroxyphenyl acetic acid (DOPAC), homovanillic acid (HVA), serotonin (5-HT), and 5-hydroxyindolyl acetic acid (5-HIAA) were determined by high-pressure liquid chromatography coupled with electrochemical detection as described (Kiss et al, 2008) and expressed in pmol/g tissue. Ratios of (DOPACϩHVA)/DA and 5-HIAA/5-HT, respectively, were calculated as an index of DA and 5-HT turnover, respectively.…”

“…In these experiments, drug-or vehicle-treated animals received NSD-1015 intraperitoneally 30 min before decapitation. DOPA levels were determined from dissected brain regions by highpressure liquid chromatography coupled with electrochemical detection (Kiss et al, 2008).…”

“…However, based on the known functions, properties, and localization of D 3 receptors, the hypothesis was developed that the presence of subnanomolar D 3 antagonism alongside nanomolar D 2 antagonism may yield an antipsychotic compound with a superior side-effect profile (e.g., reduced extrapyramidal symptoms, improvement in cognition). Indeed, representative compounds (e.g., S33138 and RG-15) developed on the basis of this idea demonstrated antipsychotic-like activity and reduced side-effect liability in animal models (Gyertyán et al, 2008;Kiss et al, 2008;Millan et al, 2008).…”

“…Previously, we hypothesized that an effective antipsychotic agent with favorable properties (such as cognition improvement) and a beneficial side-effect profile (e.g., greatly reduced liability to induce catalepsy) would combine subnanomolar affinity for dopamine D 3 receptors with nanomolar affinity for D 2 receptors Kiss et al, 2008). From a series of compounds we selected cariprazine (former code name RGH-188; Fig.…”