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Molecular Determinants of the Intrinsic Efficacy of the Antipsychotic Aripiprazole.

ABSTRACT: Partial agonists of the dopamine D2 receptor (D2R) have been developed to treat the symptoms of schizophrenia without causing the side effects elicited by antagonists. The receptor-ligand interactions that determine the intrinsic efficacy of such drugs, however, are poorly understood. Aripiprazole has an extended structure comprising a phenylpiperazine primary pharmacophore and a 1,2,3,4-tetrahydroquinolin-2-one secondary pharmacophore. We combined site-directed mutagenesis, analytical pharmacology, ligand fragments, and molecular dynamics simulations to identify the D2R-aripiprazole interactions that contribute to affinity and efficacy. We reveal that an interaction between the secondary pharmacophore of aripiprazole and a secondary binding pocket defined by residues at the extracellular portions of transmembrane segments 1, 2, and 7 determines the intrinsic efficacy of aripiprazole. Our findings reveal a hitherto unappreciated mechanism for fine-tuning the intrinsic efficacy of D2R agonists.

SUBMITTER: Klein Herenbrink C

PROVIDER: S-EPMC7365685 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Molecular Determinants of the Intrinsic Efficacy of the Antipsychotic Aripiprazole.

Klein Herenbrink Carmen C Verma Ravi R Lim Herman D HD Kopinathan Anitha A Keen Alastair A Shonberg Jeremy J Draper-Joyce Christopher J CJ Scammells Peter J PJ Christopoulos Arthur A Javitch Jonathan A JA Capuano Ben B Shi Lei L Lane J Robert JR

ACS chemical biology 20190805 8

Partial agonists of the dopamine D<sub>2</sub> receptor (D<sub>2</sub>R) have been developed to treat the symptoms of schizophrenia without causing the side effects elicited by antagonists. The receptor-ligand interactions that determine the intrinsic efficacy of such drugs, however, are poorly understood. Aripiprazole has an extended structure comprising a phenylpiperazine primary pharmacophore and a 1,2,3,4-tetrahydroquinolin-2-one secondary pharmacophore. We combined site-directed mutagenesis ...[more]

PMID: 31339684

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Project description:BACKGROUND:Aripiprazole is a relatively new antipsychotic drug, said to be the prototype of a new third generation of antipsychotics; the so-called dopamine-serotonin system stabilisers. In this review we examine how the efficacy and tolerability of aripiprazole differs from that of typical antipsychotics. OBJECTIVES:To evaluate the effects of aripiprazole compared with other typical antipsychotics for people with schizophrenia and schizophrenia-like psychoses. SEARCH STRATEGY:We searched the Cochrane Schizophrenia Group Trials Register (November 2007) which is based on regular searches of BIOSIS, CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO. We inspected references of all identified studies for further trials. We contacted relevant pharmaceutical companies, drug approval agencies and authors of trials for additional information. SELECTION CRITERIA:We included all randomised trials comparing aripiprazole with typical antipsychotics in people with schizophrenia or schizophrenia-like psychosis. DATA COLLECTION AND ANALYSIS:We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis, based on a random effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated weighted mean differences (WMD) again based on a random effects model. We have contacted representatives of Bristol Myers Squibb pharmaceuticals (UK) for additional data. MAIN RESULTS:We included nine randomised trials involving 3122 people comparing aripiprazole with typical antipsychotic drugs. None of the studies reported on relapse - our primary outcome of interest. Attrition from studies was high and data reporting poor. Participants given aripiprazole were comparable to those receiving typical drugs in improving global state and mental state. Aripiprazole provided a significant advantage over typical antipsychotics in terms of fewer occurrences of extra-pyramidal symptom (n=968, 3 RCT, RR 0.46 CI 0.3 to 0.9, NNT 13 CI 17 to 10), and particularly akathisia (n=897, 3 RCT, RR 0.39 CI 0.3 to 0.6, NNT 11 CI 14 to 9). Fewer participants given aripiprazole developed hyperprolactinaemia (n=300, 1 RCT, RR 0.07 CI 0.03 to 0.2, NNT 2 CI 3 to 1). Aripiprazole presented a lesser risk of sinus tachycardia (n=289, 1 RCT, RR 0.09 CI 0.01 to 0.8, NNT 22 CI 63 to 13) and blurred vision (n=308, 1 RCT, RR 0.19 CI 0.1 to 0.7, NNT 14 CI 25 to 10); but enhanced risk of occurrence of dizziness (n=957, 3 RCT, RR 1.88 CI 1.1 to 3.2, NNH 20 CI 33 to 14) and nausea (n=957, 3 RCT, RR 3.03 CI 1.5 to 6.1, NNH 17 CI 25 to 13). Attrition rates were high in both groups, although significantly more participants in the aripiprazole group completed the study in the long term (n=1294, 1 RCT, RR 0.81 CI 0.8 to 0.9 NNT 8 CI 5 to 14). AUTHORS' CONCLUSIONS:Aripiprazole differs little from typical antipsychotic drugs with respect to efficacy, however it presents significant advantages in terms of tolerability. Clearly reported pragmatic short, medium and long term randomised controlled trials are required to replicate and validate these findings and determine the position of aripiprazole in everyday clinical practice.

Project description:BACKGROUND AND OBJECTIVES: Aripiprazole lauroxil (AL), a long-acting injectable antipsychotic for the treatment of schizophrenia, requires 21 days of oral aripiprazole supplementation upon initiation (21-day initiation regimen). An alternative 1-day initiation regimen utilizing a nano-crystalline milled dispersion of AL (ALNCD) plus a single 30 mg oral aripiprazole dose achieved aripiprazole concentrations associated with therapeutic doses of aripiprazole in the same time frame as the 21-day initiation regimen when starting AL (441 or 882 mg). A population pharmacokinetic (PopPK) model was developed to describe aripiprazole pharmacokinetics following administration of ALNCD, AL and oral aripiprazole, and evaluate dosing scenarios likely to be encountered in clinical practice. METHODS:In total, 12,768 plasma aripiprazole concentrations from 343 patients (from 4 clinical studies) were included in the PopPK analysis and used to construct the model. RESULTS:Concomitant administration of the 1-day initiation regimen with all approved AL dosing regimens (441, 662, or 882 mg monthly, 882 mg every 6 weeks, or 1064 mg every 2 months) is predicted to achieve aripiprazole concentrations associated with therapeutic doses of AL using the 21-day initiation regimen within 4 days, maintaining these concentrations until the next AL dose. Administration of the first AL injection 10 days after the 1-day initiation regimen resulted in median aripiprazole concentrations just before the second dose of AL ≥ 77% of that when coadministered on the same day. Coadministration of AL with a single ALNCD injection was predicted to be effective in rapidly re-establishing concentrations associated with therapeutic doses of AL following dose delay. CONCLUSIONS:Model-based simulations demonstrate that the 1-day initiation regimen is suitable for starting treatment with all AL doses, allowing a window of ≤ 10 days between initiation and AL administration. ALNCD may also be used to re-establish concentrations associated with therapeutic doses of AL in conjunction with a delayed AL dose.

Project description:Aripiprazole, metformin, and paeoniae-glycyrrhiza decoction (PGD) have been widely used as adjunctive treatments to reduce antipsychotic (AP)-induced hyperprolactinemia in patients with schizophrenia. However, the comparative efficacy and safety of these medications have not been previously studied. A network meta-analysis of randomized controlled trials (RCTs) was conducted to compare the efficacy and safety between aripiprazole, metformin, and PGD as adjunctive medications in reducing AP-induced hyperprolactinemia in schizophrenia. Both international (PubMed, PsycINFO, EMBASE, and Cochrane Library databases) and Chinese (WanFang, Chinese Biomedical, and Chinese National Knowledge infrastructure) databases were searched from their inception until January 3, 2019. Data were analyzed using the Bayesian Markov Chain Monte Carlo simulations with the WinBUGS software. A total of 62 RCTs with 5,550 participants were included in the meta-analysis. Of the nine groups of treatments included, adjunctive aripiprazole (<5 mg/day) was associated with the most significant reduction in prolactin levels compared to placebo (posterior MD = -65.52, 95% CI = -104.91, -24.08) and the other eight treatment groups. Moreover, adjunctive PGD (>1:1) was associated with the lowest rate of all-cause discontinuation compared to placebo (posterior odds ratio = 0.45, 95% CI = 0.10, 3.13) and adjunctive aripiprazole (>10 mg/day) was associated with fewer total adverse drug events than placebo (posterior OR = 0.93, 95% CI = 0.65, 1.77) and other eight treatment groups. In addition, when risperidone, amisulpride, and olanzapine were the primary AP medications, adjunctive paeoniae/glycyrrhiza = 1:1, aripiprazole <5 mg/day, and aripiprazole >10 mg/day were the most effective treatments in reducing the prolactin levels, respectively. Adjunctive aripiprazole, metformin, and PGD showed beneficial effects in reducing AP-induced hyperprolactinemia in schizophrenia, with aripiprazole (<5 mg/day) being the most effective one.

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Molecular Determinants of the Intrinsic Efficacy of the Antipsychotic Aripiprazole.

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Molecular Determinants of the Intrinsic Efficacy of the Antipsychotic Aripiprazole.

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