Novel sulfonamides having dual dopamine D2 and D3 receptor affinity show in vivo antipsychotic efficacy with beneficial cognitive and EPS profile

Ágai-Csongor, Éva; Nógrádi, Katalin; Galambos, János; Vágó, István; Bielik, Attila; Magdó, Ildikó; Ignácz-Szendrei, Györgyi; Keserü, György M.; Greiner, István; Laszlovszky, István; Schmidt, Béla Kiss Éva; Sághy, Judit Laszy Katalin; Gyertyán, István; Zájer-Balázs, Mária; Gémesi, Larisza; Domány, György

doi:10.1016/j.bmcl.2007.08.015

Cited by 18 publications

(13 citation statements)

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“…Medicinal chemistry optimization of an impurity isolated during the scale-up synthesis of a pyridylsulfonamide type dopamine D 3 /D 2 compound [27] leads to a series of new piperazine derivatives having affinity to both dopamine D 3 and D 2 receptors. Cariprazine, the most promising representative of this family of compounds, showed good pharmacokinetic profile with excellent brain penetration, alleviated impairment of cognitive function in patients and did not cause catalepsy [30].…”

Section: Chemistrymentioning

confidence: 99%

“…The development of cariprazine (RGH-188, trans-N-[4-(2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl)cyclohexyl]-N',N'-dimethylurea hydrochloride; molecular formula: C 21 H 32 Cl 2 N 4 O [FIGURE 1]) arose from a systematic search for a compound with high selectivity for dopamine D 3 receptors over D 2 receptors [27]. 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.…”

Section: Chemistrymentioning

confidence: 99%

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Cariprazine, a new, orally active dopamine D_2/3receptor partial agonist for the treatment of schizophrenia, bipolar mania and depression

Veselinović

Paulzen

Gründer

2013

Expert Review of Neurotherapeutics

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Cariprazine is a novel drug with partial agonist activity at dopamine D2/3 receptors and six- to eightfold higher affinity for human dopamine D3 over D2 receptors. Results from several placebo-controlled Phase II/III trials in patients with a The Diagnostic and Statistical Manual of Mental Disorders IV diagnosis of schizophrenia or bipolar I disorder suggest that cariprazine is superior to placebo with respect to antipsychotic and antimanic activity. Reports concerning safety and tolerability of cariprazine are mainly favorable, although the rates of treatment-associated adverse events, which most commonly included akathisia and extrapyramidal symptom, are rather high. However, only minor alterations of clinical laboratory values, prolactin concentrations and ECG parameters are reported in cariprazine-treated patients. A new drug application to the U.S. F DA for cariprazine for the treatment of both schizophrenia and manic or mixed episodes associated with bipolar I disorder was submitted in November 2012. A more precise assessment of the clinical properties of this new drug will require additional studies, aimed to compare and contrast cariprazine with other antipsychotic agents.

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Section: Chemistrymentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Cariprazine, a new, orally active dopamine D_2/3receptor partial agonist for the treatment of schizophrenia, bipolar mania and depression

Veselinović

Paulzen

Gründer

2013

Expert Review of Neurotherapeutics

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“…Researchers at Gedeon Richter institute undertook an alternative approach to discover novel antipsychotics with combined high affinity for D 3 R and D 2 R beginning with SB-277011 (selective D 3 R antagonists) [98,99]. The replacement of the 6-cyanotetrahydroisoquinoline moiety with 2,3-diClPhP and the …”

Section: Long-chain Arylpiperazine Derivatives: From Selective D 3 Anmentioning

confidence: 99%

Quinoline- and Isoquinoline-Sulfonamide Analogs of Aripiprazole: Novel Antipsychotic Agents?

et al. 2013

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The introduction of typical antipsychotics over six decades ago signaled an important milestone in psychiatry. However, second-generation antipsychotics ameliorated the positive symptoms of schizophrenia but displayed limited effectiveness for the negative and cognitive symptoms. In addition, while the newer antipsychotics produced fewer motor side effects, the atypical antipsychotics still induced weight gain and endocrinopathies. In recent years, a third generation of antipsychotics was identified. Aripiprazole was the first approved drug acting as a D2 partial agonist/functionally selective ligand. This review presents the state of the development of novel antipsychotic dopaminergic and non-dopaminergic agents, supported by an overview of the compounds evaluated under advanced preclinical and clinical development (e.g., cariprazine and brexpiprazole). In line with the recent trends in the development of modern atypical antipsychotics, we present our strategic development of long-chain arylpiperazine-derived quinoline- and isoquinoline-sulfonamide displaying a multireceptor binding profile and partial D2 receptor agonism.

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“…Moreover, D3R antagonists have been shown to enhance D3 receptor mediated release of acetylcholine in the frontal cortex and, therefore, may have beneficial effects on attention and memory loss associated with schizophrenia . Indeed, studies with D3R selective or D3R preferring antagonists have confirmed their efficacy as antipsychotic and procognitive agents. − …”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Structure–Activity Relationship Studies of a Series of [4-(4-Carboxamidobutyl)]-1-arylpiperazines: Insights into Structural Features Contributing to Dopamine D3 versus D2 Receptor Subtype Selectivity

et al. 2014

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Antagonist and partial agonist modulators of the dopamine D3 receptor (D3R) have emerged as promising therapeutics for the treatment of substance abuse and neuropsychiatric disorders. However, development of druglike lead compounds with selectivity for the D3 receptor has been challenging because of the high sequence homology between the D3R and the dopamine D2 receptor (D2R). In this effort, we synthesized a series of acylaminobutylpiperazines incorporating aza-aromatic units and evaluated their binding and functional activities at the D3 and D2 receptors. Docking studies and results from evaluations against a set of chimeric and mutant receptors suggest that interactions at the extracellular end of TM7 contribute to the D3R versus D2R selectivity of these ligands. Molecular insights from this study could potentially enable rational design of potent and selective D3R ligands.

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Novel sulfonamides having dual dopamine D2 and D3 receptor affinity show in vivo antipsychotic efficacy with beneficial cognitive and EPS profile

Cited by 18 publications

References 1 publication

Cariprazine, a new, orally active dopamine D_2/3receptor partial agonist for the treatment of schizophrenia, bipolar mania and depression

Cariprazine, a new, orally active dopamine D_2/3receptor partial agonist for the treatment of schizophrenia, bipolar mania and depression

Quinoline- and Isoquinoline-Sulfonamide Analogs of Aripiprazole: Novel Antipsychotic Agents?

Design, Synthesis, and Structure–Activity Relationship Studies of a Series of [4-(4-Carboxamidobutyl)]-1-arylpiperazines: Insights into Structural Features Contributing to Dopamine D3 versus D2 Receptor Subtype Selectivity

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Novel sulfonamides having dual dopamine D2 and D3 receptor affinity show in vivo antipsychotic efficacy with beneficial cognitive and EPS profile

Cited by 18 publications

References 1 publication

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

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

Quinoline- and Isoquinoline-Sulfonamide Analogs of Aripiprazole: Novel Antipsychotic Agents?

Design, Synthesis, and Structure–Activity Relationship Studies of a Series of [4-(4-Carboxamidobutyl)]-1-arylpiperazines: Insights into Structural Features Contributing to Dopamine D3 versus D2 Receptor Subtype Selectivity

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Cariprazine, a new, orally active dopamine D_2/3receptor partial agonist for the treatment of schizophrenia, bipolar mania and depression

Cariprazine, a new, orally active dopamine D_2/3receptor partial agonist for the treatment of schizophrenia, bipolar mania and depression