Description
Aripiprazole was launched for the treatment of psychoses including schizophrenia and
offers a novel mechanism of action as a partial D2 receptor agonist. Aripiprazole can be
synthesized in three steps beginning by the condensation of 7-hydroxy-1,2,3,4-
tetrahydroquinolin-2-one with 1 ,Cdibromobutane followed by reaction with 1-(2,3-
dichlorophenyl)piperazine. Aripiprazole is a significant D2 agonist/antagonist, 5-HT2
antagonist and 5-HT1α agonist combined with minimal affinity for a,-adrenergic, H1 and M1
receptors. It has a low D4:D2 selectivity ratio and a D2:5-HT2 affinity ratio that exceeds 15;
resulting in different pharmacological characteristics compared to other atypical
antipsychotics agents such as clozapine. In animal models, aripiprazole inhibits
apomorphine-induced stereotypy without causing catalepsy and ptosis. Moreover, in
contrast to classical antipsychotics that produce disabling movement disorders, aripiprazole does not cause an upregulation of D2 receptors or an increase in immediate
early gene expression of e.g. the c-fos mRNA in the striatum. In patients with acute
relapse of schizophrenia, treatment with aripiprazole provided significant improvement in
both positive and negative syndrome scale (PANSS) total score in both short- and longterm
evaluations. These results were comparable to those observed with haloperidol or
risperidone; however, the early response rate was greater with aripiprazole. Aripiprazole
was well tolerated with mild to moderate adverse events such as nausea, dizziness,
somnolence and weight gain. The rates of extrapyramidal symptoms were lower than with
haloperidol, prolactin levels increase has been uncommon and no significant Q-Tc interval
prolongation was observed compared with placebo. Finally, studies suggested a minimal
impact of aripiprazole administration on total cholesterol levels and on fasting blood sugar
in contrast to other antipsychotics. Aripiprazole has a bioavailability of 87%, a tmax of 3-5 h
and a half-life time of 48-68 h. Aripiprazole has been found to have linear kinetics and is
mainly metabolized via the cytochrome systems CYP2D6 and CYP3A4. It has little effect
on the blood levels of other medications; interaction with both lithium and divalproex
sodium found minimal impact. Aripiprazole has also been studied in other psychiatric
disorders, including bipolar disorders and has shown great efficacy.
Chemical Properties
Colourless Flake Crystalline Solid
Originator
Otsuka (Japan)
Definition
ChEBI: Aripiprazole is an N-arylpiperazine that is piperazine substituted by a 4-[(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy]butyl group at position 1 and by a 2,3-dichlorophenyl group at position 4. It is an antipsychotic drug used for the treatment of Schizophrenia, and other mood disorders. It has a role as a H1-receptor antagonist, a serotonergic agonist, a second generation antipsychotic and a drug metabolite. It is a quinolone, a N-arylpiperazine, a N-alkylpiperazine, a dichlorobenzene, an aromatic ether and a delta-lactam.
Manufacturing Process
To a solution of 4.06 g of K2CO3 with 400 ml of water was added 40 g of 7-
hydroxy-3,4-dihydrocarbostyril [1] and 158 g of 1,4-dibrombutane. The
mixture was refluxed for 3 hours. Then it was extracted with dichloremethane,
dried with anhydrous MgSO4, the solvent was removed by evaporation. The
residue was purified by means of silica gel chromatography (eluent:
dichloromethane) and recrystallized from n-hexane-ethanol to yield 50 g of 7-
(4-bromobutoxy)-3,4-dihydrocarbostyril, mp 110.5°-110.0°C.
47 g of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril, 35 g of NaJ in 600 ml of
acetonitrile was refluxed for 30 minutes. To this suspension was added 40 g of
1-(2,3-dichlorophenyl)piperazine (it was prepareted from 2,3-chloroaniline and
di(2-bromoethyl)amine [1]) and 33 ml of triethylamine. The mixture was
refluxed for 3 hours. After removing of the solvent, the residue was dissolved
in chloroform, washed with water and dried with anhydrous MgSO4. The
solvent was removed by evaporation, and residue was recrystallized from
ethanol twice to yield 57.1 g of 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-
butoxy}-3,4-dihydrocarbostyril. Melting point: 139.0°-139.5°C.
Brand name
Abilify (Otsuka).
Therapeutic Function
Antipsychotic
General Description
Aripiprazole (Abilify). The newest, longactingaripiprazole (an arylpiperazine quinolinone derivative),appears to be partial agonist of D2 receptors (i.e., itstimulates certain D2 receptors while blocking others dependingon their locations in the brain and the concentrationof drug). Bioavailability of aripiprazole is around 87%, with peak plasma concentration attained at 3 to 5 hours afterdosing. It is metabolized by dehydrogenation, oxidative hydroxylation, and N-dealkylation, largelymediated by hepatic CYPs 3A4 and 2D6.
The diphenylbutylpiperidine class can be considered amodification of the fluorobutyrophenone class. Because oftheir high lipophilicity, the compounds are inherently longacting. Pimozide has been approved for antipsychotic use,and penfluridol has undergone clinical trials in the UnitedStates. Overall, side effects for the two compounds resemblethose produced by the fluorobutyrophenones.
General Description
Aripiprazole, (7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)-quinolone,is an atypical antipsychotic that is available in tablets(Abilify), orally disintegrating tablets (Abilify Discmelt), anda 1-mg/mL oral solution. Unlike the other atypical antipsychotics,aripiprazole exhibits partial agonist activity at D2, D3,D4, and 5-HT1A receptors, and antagonist action at 5-HT2A receptors.Although aripiprazole exhibits a low incidence ofEPS, the compound occupies about 95% of striatal D2 receptorsat therapeutic doses. Additionally, aripiprazole does nothave a fast rate of dissociation from D2 receptors. Althoughthe mechanism of action of this compound remains to be elucidated,the atypical profile for aripiprazole may be related toits action at other monoamine receptors.The compoundis well absorbed with peak plasma levels occurring 3 to 5hours after oral administration. Food does not affect absorptionof aripiprazole. Aripiprazole is extensively metabolizedin the liver by the action of CYP2D6 and CYP3A4. The primarymetabolite in humans is dehydroaripiprazole. This metabolite represents about 40% of aripiprazoleat steady state.In the presence of CYP3A4 and CYP2D6 inhibitorsor inducers, dosage adjustments of aripiprazole maybe required. The mean elimination half-lives in extensive andpoor metabolizers are 75 hours and 146 hours, respectively.The major adverse effects of aripiprazole are headache, anxiety,and insomnia.Similar to other atypical antipsychotics,aripiprazole shows an increased risk in mortality in elderlypatients with dementia-related psychosis.Aripiprazoledemonstrates a different pharmacological profile from allother atypical antipsychotics.
Biochem/physiol Actions
Aripiprazole is a second generation atypical antipsychotic and anti-depressant with partial agonist activity at dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at serotonin 5-HT2A receptors. Ki values are 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively, for dopamine D2 and D3, serotonin 5-HT1A and 5-HT2A receptors. Aripiprazole is used in the treatment of schizophrenia.
Clinical Use
Atypical antipsychotic:
Treatment of schizophrenia
Depression in bipolar disorder
Safety Profile
A poison by intravenous route.When heated to decomposition it emits toxic vapors ofNOx and Cl-.
Metabolism
Aripiprazole is extensively metabolised by the liver
primarily by three biotransformation pathways:
dehydrogenation, hydroxylation, and N-dealkylation.
Based on in vitro studies, CYP3A4 and CYP2D6
enzymes are responsible for dehydrogenation and
hydroxylation of aripiprazole, and N-dealkylation is
catalysed by CYP3A4. Aripiprazole is the main active
moiety in systemic circulation. At steady state, dehydroaripiprazole, the active metabolite, represents about 40%
of aripiprazole AUC in plasma.
Following a single oral dose of [14C]-aripiprazole,
approximately 27% of the administered radioactivity
was recovered in the urine and approximately 60% in
the faeces. Less than 1% of unchanged aripiprazole
was excreted in the urine and approximately 18% was
recovered unchanged in the faeces.
References
1) Green et al. (2004), Focus on aripiprazole; Curr. Med. Res. Opin., 20 207
2) Kikuchi et al. (1995), 7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-2(1H)-quinolinone (OPC-14597), a new putative antipsychotic drug with both presynaptic dopamine autoreceptor agonistic activity and postsynaptic D2 receptor antagonistic activity; J. Pharmacol. Exp. Ther., 274 329
3) Madhusoodanan et al. (2008), Management of psychosis in patients with Alzheimer’s disease: focus on aripiprazole; Clin. Interv. Aging, 3 491
4) Feltenstein et al. (2007), Aripiprazole blocks reinstatement of cocaine seeking in an animal model of relapse; Biol. Psychiatry, 61 582
