<p>Preclinical pharmacodynamic and pharmacokinetic characterization of the major metabolites of cariprazine</p>

Abstract

Introduction: Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, has two major human metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR). The metabolite pharmacology was profiled to understand the contribution to cariprazine efficacy.MethodsIn vitro receptor binding and functional assays, electrophysiology, animal models, microdialysis, and kinetic-metabolism approaches were used to characterize the pharmacology of DCAR and DDCAR. ResultsSimilar to cariprazine, both metabolites showed high affinity for human D3, D2L, 5-HT1A, 5-HT2A, and 5-HT2B receptors, albeit with higher selectivity than cariprazine for D3 versus D2 receptors. In [35S]GTPγS binding assays, cariprazine and DDCAR were antagonists in membranes from rat striatum and from cells expressing human D2 and D3 receptors, and were partial agonists in membranes from rat hippocampus. In cAMP signaling assays, cariprazine, DCAR, and DDCAR acted as partial agonists at D2 and D3 receptors; cariprazine and DDCAR were full agonists, whereas DCAR was a partial agonist at 5-HT1A receptors. Cariprazine, DCAR, and DDCAR were pure antagonists at human 5-HT2B receptors. Cariprazine and DDCAR increased rat striatal dopamine and reduced cortical serotonin turnover. Cariprazine and DDCAR showed similar in vivo D3 receptor occupancy in rat brain; however, cariprazine was more potent for D2 receptor occupancy. Both cariprazine and DDCAR dose-dependently but partially suppressed the spontaneous activity of midbrain dopaminergic neurons in rats, with the parent compound being more potent but shorter acting than its metabolite. Consistent with the D2 receptor occupancy profile, DDCAR was 3- to 10-fold less potent than cariprazine in rodent models of antipsychotic-like activity. Following acute cariprazine administration, DDCAR was detected in the rodent brain but at much lower levels than cariprazine.ConclusionOverall, in vitro and in vivo pharmacological profiles of DCAR and DDCAR demonstrated high similarity with cariprazine, suggesting that the major metabolites of cariprazine contribute significantly to its clinical efficacy.

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

“…Some compounds can increase basal DA release in the prefrontal cortex and striatum such as the D3R preferring D2/D3 antagonist IRL-790 also known as mesodopetam [ 244 ]. The D3R preferring partial agonist cariprazine increases DA release in the nucleus accumbens and ventral hippocampus [ 245 ] as well as DA turnover in the striatum [ 204 ] in intact animals. Cariprazine also increases DA release in the prefrontal cortex in a PCP-exposure model of acute psychosis [ 246 ].…”

“…A study by Millan et al (2010) [201] shows that the D3R preferring antagonist S33138 improves cognitive performance in Rhesus monkeys. Not only full antagonists (agents without intrinsic activity), but also compounds that are D3R preferring partial agonists (functioning as antagonists under high dopaminergic tone) such as BP-897, cariprazine, or its metabolite, didesmethyl-cariprazine also improve cognitive deficits in various animal models [150,194,[204][205][206] (Table 4). In case of cariprazine this pro-cognitive action translates well into humans, as it improved cognition in schizophrenic patients, which is not typical to antipsychotics [207].…”

Cariprazine as a treatment across the bipolar I spectrum from depression to mania: mechanism of action and review of clinical data

“…10 What this means is that the actions of DDCAR, which has the same, if not more potent, actions on neurotransmitter receptor binding, is responsible for efficacy and tolerability. 22 Thus, on the one hand, effective cariprazine dose may rise over several weeks even though daily dosing stays the same; on the other hand, missing a dose may not be a devastating event. In fact, cariprazine is the only antipsychotic with recommended every-other-day dosing (when cariprazine is taken in the presence of a strong CYP3A4 inhibitor).…”

Cariprazine modulates sleep architecture in rats

“…In this study, the EEG modulatory effect of cariprazine was most prominent at the 0.3 mg/kg dose, which is in accordance with the pharmacologically active dose range described in the paper by Gyertyán et al (2011) for behavioural endpoints. Furthermore, occupancy findings for cariprazine, described in a recent paper (Kiss et al, 2019), revealed ED 50 values of 0.23 and 0.43 mg/kg for the inhibition of striatal dopamine D 2 receptor and cerebellar dopamine D 3 receptor binding, respectively. It is therefore reasonable to assume that the effects of cariprazine on the sleep EEG could be attributed to its interactions with these dopamine receptors.…”