Cariprazine

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Cariprazine
Cariprazine.svg
Systematic (IUPAC) name
N​ '-[trans-4-[2-[4-(2,3-dichlorophenyl)-1-piperazinyl]ethyl]cyclohexyl]-N,N-dimethylurea
Clinical data
Legal status Investigational
Routes Oral
Pharmacokinetic data
Bioavailability High
Metabolism Hepatic via CYP3A4 & to a lesser extent, CYP2D6
Half-life 2-5 days (2-3 wks for active metabolite, desmethylcariprazine)
Identifiers
CAS number 839712-12-8
ATC code ?
PubChem CID 135626718
ChemSpider 25999972 YesY
KEGG D09997 YesY
Chemical data
Formula C21H32Cl2N4O 
Mol. mass 427.411 g/mol
Mechanism of cariprazine action as antagonist or agonist.

Cariprazine (RGH-188) is an antipsychotic drug under development by Gedeon Richter. It acts as a D2 and D3 receptor partial agonist, with high selectivity towards the D3 receptor.[1] Positive Phase III study results were published for schizophrenia and mania early 2012, while Phase II studies in bipolar disorder I, and for bipolar depression are in progress.[2] Action on the dopaminergic systems makes it also potentially useful as an add-on therapy in major depressive disorder [3]

Forest Laboratories obtained a license on development (from the Richter - Hungary) and exclusive commercial rights in the US in 2004.

Medical uses[edit]

Cariprazine is currently in clinical trials for schizophrenia and bipolar disorder. It has also been investigated as a potential adjunct in treatment-resistant major depressive disorder.[4]

Side effects[edit]

The most prevalent side effects for cariprazine include akathisia, insomnia, and weight gain. In Phase III trial for schizophrenia, 66.7 % of patients experienced these side effects, as well as other issues such as metabolic problems, extrapyramidal side effects (EPSE), and sedation. This suggests that cariprazine might not make it past Phase III testing for schizophrenia because its tolerability is lower than those of its competitors.[5] Other medications cause many motor defects and EPSE, which are major problems for patients who did not have motor issues before taking the medicine.[6] These motor issues are due to the fact that dopamine acts on the motor pathway as well as the reward pathway, and many antipsychotics stimulate dopamine pathway, causing excessive motor movement as well as the intended effects.

These side effects are considerably lower in the Phase III trials for bipolar disorder I (for unknown reasons).[5]

Pharmacodynamics[edit]

Cariprazine acts as an antipsychotic that is effective against the positive and negative symptoms of schizophrenia.[7] Unlike many antipsychotics that are D2 and 5-HT2A receptor antagonists, cariprazine is a D2 and D3 partial agonist. It also has a higher affinity for D3 receptors. The D2 and D3 receptors are important targets for the treatment of schizophrenia, because the overstimulation of dopamine receptors has been implicated as a possible cause of schizophrenia.[8] Cariprazine acts to inhibit overstimulated dopamine receptors (acting as an antagonist) and stimulate the same receptors when the endogenous dopamine levels are low. Cariprazine’s high selectivity towards D3 receptors could prove to reduce side effects associated with the other antipsychotic drugs, because D3 receptors are mainly located in the ventral striatum and would not incur the same motor side effects (extrapyramidal symptoms) as drugs that act on dorsal striatum dopamine receptors.[7] Cariprazine also acts on 5-HT1A receptors, though the affinity is considerably lower than the affinity to dopamine receptors (seen in monkey and rat brain studies).[7][9] In the same studies, cariprazine has been noted to produce pro-cognitive effects, the mechanisms of which are currently under investigation. An example of pro-cognitive effects occurred in pre-clinical trials with rats: rats with cariprazine performed better in a scopolamine-induced learning impairment paradigm in a water labyrinth test. This may be due to the selective antagonist nature of D3 receptors, though further studies need to be conducted.[7] This result could be very useful for schizophrenia, as one of the symptoms includes cognitive deficits.

Cariprazine has partial agonist as well as antagonist properties depending on the endogenous dopamine levels. When endogenous dopamine levels are high (as is hypothesized in schizophrenic patients), cariprazine acts as an antagonist by blocking dopamine receptors. When endogenous dopamine levels are low, cariprazine acts more as an agonist, increasing dopamine receptor activity.[10] In monkey studies, the administration of increasing does of cariprazine resulted in a dose-dependent and saturable reduction of specific binding. At the highest dose (300 μg/kg), the D2/D3 receptors were 94 % occupied, while at the lowest dose (1 μg/kg), receptors were 5 % occupied.[9]

Receptor Ki (nM)[4] Pharmacodynamic action[4]
5-HT1A 3 Partial agonism
5-HT2A 19 Inverse agonism/antagonism
5-HT2B 0.58 Inverse agonism/Antagonism
5-HT2C 134 Inverse agonism/Antagonism
5-HT7 111 Antagonism
D2S 0.69 Partial agonism
D2L 0.49 Partial agonism
D3 0.085 Partial agonism
H1 23 Inverse agonism/antagonism

Pharmacokinetics[edit]

Cariprazine has high oral bioavailability and can cross the blood brain barrier easily in humans because it is lipophilic.[2] In rats, the oral bioavailability was 52 % (with a dose of 1 mg/kg).[6]

References[edit]

  1. ^ Kiss B; Horváth A; Némethy Z; Schmidt E; Laszlovszky I; Bugovics G; Fazekas K; Hornok K; Orosz S; Gyertyán I; Agai-Csongor E; Domány G; Tihanyi K; Adham N; Szombathelyi Z (2010). "Cariprazine (RGH-188), a dopamine D(3) receptor-preferring, D(3)/D(2) dopamine receptor antagonist-partial agonist antipsychotic candidate: in vitro and neurochemical profile". The Journal of Pharmacology and Experimental Therapeutics 333 (1): 328–340. doi:10.1124/jpet.109.160432. PMID 20093397. 
  2. ^ a b Gründer G (2010). "Cariprazine, an orally active D2/D3 receptor antagonist, for the potential treatment of schizophrenia, bipolar mania and depression". Current Opinion in Investigational Drugs 11 (7): 823–832. PMID 20571978. 
  3. ^ Clinical trial : Safety and Efficacy of Caripazine As Adjunctive Therapy In Major Depressive Disorder
  4. ^ a b c Citrome, L (February 2013). "Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability". Expert Opinion on Drug Metabolism and Toxicology 9 (2): 193–206. doi:10.1517/17425255.2013.759211. PMID 23320989. 
  5. ^ a b "APA 2012: cariprazine fails to offer a therapeutic breakthrough". Datamonitor Research Store. 2012-05-15. Retrieved 2014-03-30. 
  6. ^ a b Newman-Tancredi, A.; Kleven, MS. (Aug 2011). "Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties.". Psychopharmacology (Berlin) 216 (4): 451–73. doi:10.1007/s00213-011-2247-y. PMID 21394633. 
  7. ^ a b c d Gyertyán, I.; Kiss, B.; Sághy, K.; Laszy, J.; Szabó, G.; Szabados, T.; Gémesi, LI.; Pásztor, G. et al. (Nov 2011). "Cariprazine (RGH-188), a potent D3/D2 dopamine receptor partial agonist, binds to dopamine D3 receptors in vivo and shows antipsychotic-like and procognitive effects in rodents.". Neurochemistry International 59 (6): 925–35. doi:10.1016/j.neuint.2011.07.002. PMID 21767587. 
  8. ^ Seeman, P.; Kapur, S. (Jul 2000). "Schizophrenia: more dopamine, more D2 receptors.". Proceedings of the National Academy of the Sciences of the United States of America 97 (14): 7673–5. PMC 33999. PMID 10884398. 
  9. ^ a b Seneca, N.; Finnema, SJ.; Laszlovszky, I.; Kiss, B.; Horváth, A.; Pásztor, G.; Kapás, M.; Gyertyán, I. et al. (Dec 2011). "Occupancy of dopamine D₂ and D₃ and serotonin 5-HT₁A receptors by the novel antipsychotic drug candidate, cariprazine (RGH-188), in monkey brain measured using positron emission tomography.". Psychopharmacology (Berlin) 218 (3): 579–87. doi:10.1007/s00213-011-2343-z. PMC 3210913. PMID 21625907. 
  10. ^ Citrome, L (February 2013). "Cariprazine in Schizophrenia: Clinical Efficacy, Tolerability, and Place in Therapy". Advances in Therapy 30 (2): 114–126. doi:10.1007/s12325-013-0006-7. PMID 23361833.