Discovery of cariprazine (RGH-188): a novel antipsychotic acting on dopamine D3/D2 receptors.

  title={Discovery of cariprazine (RGH-188): a novel antipsychotic acting on dopamine D3/D2 receptors.},
  author={{\'E}va {\'A}gai-Csongor and G. Domány and K. N{\'o}gr{\'a}di and J. Galambos and I. V{\'a}g{\'o} and G. Keserű and I. Greiner and I. Laszlovszky and A. Gere and {\'E}. Schmidt and B. Kiss and M. Vastag and K. Tihanyi and K. Sághy and J. Laszy and I. Gyertyán and M{\'a}ria Z{\'a}jer-Bal{\'a}zs and L. Gémesi and M. Kapás and Z. Szombathelyi},
  journal={Bioorganic \& medicinal chemistry letters},
  volume={22 10},
Medicinal chemistry optimization of an impurity isolated during the scale-up synthesis of a pyridylsulfonamide type dopamine D(3)/D(2) compound (1) led to a series of new piperazine derivatives having affinity to both dopamine D(3) and D(2) receptors. Several members of this group showed excellent pharmacokinetic and pharmacodynamic properties as demonstrated by outstanding activities in different antipsychotic tests. The most promising representative, 2m (cariprazine) had good absorption… Expand
Discovery of Cariprazine (RGH‐188): A Novel Antipsychotic Acting on Dopamine D3/D2 Receptors.
Medicinal chemistry optimization of an impurity isolated during the scale-up synthesis of a pyridylsulfonamide-type compound as a high-affinity dopamine D3/D2 receptor ligand leads to a series of newExpand
A new generation of antipsychotics: pharmacology and clinical utility of cariprazine in schizophrenia
Well-designed clinical trials, mainly direct “head-to-head” comparisons with other second-generation antipsychotic agents, are needed to define the therapeutic role and safety profile of cariprazine in schizophrenia and bipolar mania. Expand
A structure-activity analysis of biased agonism at the dopamine D2 receptor.
It is demonstrated that efficacy and biased agonism can be finely tuned by minor structural modifications to the head group containing the tertiary amine, a tail group that extends away from this moiety, and the orientation and length of a spacer region between these two moieties. Expand
Quinoline- and isoquinoline-sulfonamide analogs of aripiprazole: novel antipsychotic agents?
This review presents the state of the development of novel antipsychotic dopaminergic and non-dopaminergic agents and presents the strategic development of long-chain arylpiperazine-derived quinoline- and isoquinoline-sulfonamide displaying a multireceptor binding profile and partial D2 receptor agonism. Expand
Design, synthesis and molecular modelling of new bulky Fananserin derivatives with altered pharmacological profile as potential antidepressants.
It is now known that many neurotransmitter systems are responsible for diseases of the central nervous system (CNS). One of the most common CNS disease is depression. Considering that in theExpand
Clinical potential of cariprazine in the treatment of acute mania.
The aim of this article is to review the potential use of cariprazine for the treatment of acute manic episodes in the light of the preclinical and clinical trials reported to date. Expand
Beyond small-molecule SAR: using the dopamine D3 receptor crystal structure to guide drug design.
This chapter will highlight recent preclinical and clinical studies demonstrating potential utility of D3 receptor-selective ligands in the treatment of addiction, and new structure-based rational drug design strategies that complement traditional small-molecule SAR to improve the selectivity and directed efficacy profiles are examined. Expand
Design and synthesis of dual 5-HT1A and 5-HT7 receptor ligands.
Compound 16, a butyrophenone derivative of tetrahydroisoquinoline (THIQ), was identified as the most potent agent with low nanomolar binding affinities to both receptors and it is anticipated that compound 16 may serve as a lead for further exploitation in the quest to identify new ligands with the potential to treat diseases of CNS origin. Expand
The preclinical discovery and development of cariprazine for the treatment of schizophrenia
This review article focuses on the preclinical discovery of cariprazine providing details regarding its pharmacological, behavioral, and neurochemical mechanisms and its contribution to clinical therapeutic benefits. Expand
Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability
  • L. Citrome
  • Medicine
  • Expert opinion on drug metabolism & toxicology
  • 2013
The chemistry, pharmacodynamic profile, pharmacokinetics, and clinical profile of cariprazine, an atypical antipsychotic in clinical development for the treatment of schizophrenia and bipolar mania/mixed episodes, are described. Expand


Recent Advances in the Development of Dopamine D3 Receptor Antagonists: a Medicinal Chemistry Perspective
A clear trend towards the optimization of the developability properties of the new scaffold has clearly emerged with time, from both academic and industrial researchers. Expand
Novel sulfonamides having dual dopamine D2 and D3 receptor affinity show in vivo antipsychotic efficacy with beneficial cognitive and EPS profile.
A novel series of arylsulfonamides was prepared and the most interesting representative, compound 2, showed potent antipsychotic behaviour coupled with a beneficial cognitive and EPS profile. Expand
Dopamine D3 receptor ligands: recent advances in the control of subtype selectivity and intrinsic activity.
Recently developed structural classes of D(3) ligands are discussed, which cover a broad spectrum of intrinsic activities and show interesting selectivities. Expand
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
The distinct in vivo profile of cariprazine may be due to its higher affinity and in vivo binding to D(3) receptors versus currently marketed typical and atypical antipsychotics. Expand
Cariprazine (RGH-188), a Dopamine D3 Receptor-Preferring, D3/D2 Dopamine Receptor Antagonist–Partial Agonist Antipsychotic Candidate: In Vitro and Neurochemical Profile
The antagonist–partial agonist properties of cariprazine at D3 and D2 receptors, with very high and preferential affinity to D3 receptors, make it a candidate antipsychotic with a unique pharmacological profile among known antipsychotics. Expand
Subnanomolar dopamine D3 receptor antagonism coupled to moderate D2 affinity results in favourable antipsychotic-like activity in rodent models: II. behavioural characterisation of RG-15
The results suggest that subnanomolar dopamine D3 receptor antagonism coupled to moderate D2 affinity may result in an antipsychotic profile characterised by a lack of extrapyramidal side effects and secondary negative symptoms with simultaneous efficacy on positive and cognitive symptoms of schizophrenia. Expand