Dual ligands targeting dopamine D2 and serotonin 5-HT 1A receptors as new antipsychotical or anti-parkinsonian agents

Na Ye, Zilan Song, Ao Zhang

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Psychiatric disorders like schizophrenia and neurodegenerative diseases like Parkinson's disease are associated with poly-factorial pathogenic mechanisms, with several neurotransmitter systems closely involved. In addition to the cerebral dopaminergic (DA) system, the serotoninergic (5-HT) system also plays a crucial role in regulating psychoemotional, cognitive and motor functions in the central nervous system (CNS). Among the large 5-HT receptor family, accumulating data have revealed new insights into the therapeutic benefit of the 5-HT1A receptor in treating various CNS disorders, especially schizophrenia and Parkinson's disease. The present review discusses the advance of dual agents with mixed actions at the dopamine D2 and serotonin 5-HT1A receptors in the treatment of these diseases. Aripiprazole was the only marketed drug with dual D2 and 5-HT 1A profile. It is a partial D2 and 5-HT1A receptor agonist and has been prescribed as an atypical antipsychotical drug. Two other drugs Cariprazine and Pardoprunox are being investigated in clinic. Most of the other candidate compounds, including Bifeprunox, Sarizotan, Mazapertine succinate, PF-217830, and Adoprazine were discontinued due to either non-optimal pharmacokinetic properties or insufficient therapeutical efficacy. Although much effort has been done to highlight the advantages of the 5-HT 1A and D2 dual approach, it has to be pointed out that many of these drugs showed poly-pharmacological profile by targeting many other receptors and/or transporters besides the D2 and 5-HT1A receptors. In this regard, 'pure' compounds exclusively acting on the D 2 and 5-HT1A receptors are highly needed to further validate this approach. Meanwhile, safety concerns and in vivo pharmacokinetic alerts should also be implanted to the drug design art early.

Original languageEnglish (US)
Pages (from-to)437-457
Number of pages21
JournalCurrent Medicinal Chemistry
Volume21
Issue number4
DOIs
StatePublished - Feb 2014
Externally publishedYes

Fingerprint

Receptor, Serotonin, 5-HT1A
Dopamine
Serotonin
Ligands
Pharmacokinetics
Pharmaceutical Preparations
Neurology
Parkinson Disease
Schizophrenia
Neurodegenerative diseases
Serotonin 5-HT1 Receptor Agonists
Serotonin Receptors
Drug Design
Central Nervous System Diseases
Art
Neurodegenerative Diseases
Cognition
Neurotransmitter Agents
Psychiatry
Central Nervous System

Keywords

  • Atypical antipsychotics
  • Dopamine D receptor
  • Dual ligands
  • Parkinson's disease
  • Schizophrenia
  • Serotonin 5-HT receptor

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Dual ligands targeting dopamine D2 and serotonin 5-HT 1A receptors as new antipsychotical or anti-parkinsonian agents. / Ye, Na; Song, Zilan; Zhang, Ao.

In: Current Medicinal Chemistry, Vol. 21, No. 4, 02.2014, p. 437-457.

Research output: Contribution to journalArticle

@article{c77e3cdc243e443698ef3e7721fdd055,
title = "Dual ligands targeting dopamine D2 and serotonin 5-HT 1A receptors as new antipsychotical or anti-parkinsonian agents",
abstract = "Psychiatric disorders like schizophrenia and neurodegenerative diseases like Parkinson's disease are associated with poly-factorial pathogenic mechanisms, with several neurotransmitter systems closely involved. In addition to the cerebral dopaminergic (DA) system, the serotoninergic (5-HT) system also plays a crucial role in regulating psychoemotional, cognitive and motor functions in the central nervous system (CNS). Among the large 5-HT receptor family, accumulating data have revealed new insights into the therapeutic benefit of the 5-HT1A receptor in treating various CNS disorders, especially schizophrenia and Parkinson's disease. The present review discusses the advance of dual agents with mixed actions at the dopamine D2 and serotonin 5-HT1A receptors in the treatment of these diseases. Aripiprazole was the only marketed drug with dual D2 and 5-HT 1A profile. It is a partial D2 and 5-HT1A receptor agonist and has been prescribed as an atypical antipsychotical drug. Two other drugs Cariprazine and Pardoprunox are being investigated in clinic. Most of the other candidate compounds, including Bifeprunox, Sarizotan, Mazapertine succinate, PF-217830, and Adoprazine were discontinued due to either non-optimal pharmacokinetic properties or insufficient therapeutical efficacy. Although much effort has been done to highlight the advantages of the 5-HT 1A and D2 dual approach, it has to be pointed out that many of these drugs showed poly-pharmacological profile by targeting many other receptors and/or transporters besides the D2 and 5-HT1A receptors. In this regard, 'pure' compounds exclusively acting on the D 2 and 5-HT1A receptors are highly needed to further validate this approach. Meanwhile, safety concerns and in vivo pharmacokinetic alerts should also be implanted to the drug design art early.",
keywords = "Atypical antipsychotics, Dopamine D receptor, Dual ligands, Parkinson's disease, Schizophrenia, Serotonin 5-HT receptor",
author = "Na Ye and Zilan Song and Ao Zhang",
year = "2014",
month = "2",
doi = "10.2174/09298673113206660300",
language = "English (US)",
volume = "21",
pages = "437--457",
journal = "Current Medicinal Chemistry",
issn = "0929-8673",
publisher = "Bentham Science Publishers B.V.",
number = "4",

}

TY - JOUR

T1 - Dual ligands targeting dopamine D2 and serotonin 5-HT 1A receptors as new antipsychotical or anti-parkinsonian agents

AU - Ye, Na

AU - Song, Zilan

AU - Zhang, Ao

PY - 2014/2

Y1 - 2014/2

N2 - Psychiatric disorders like schizophrenia and neurodegenerative diseases like Parkinson's disease are associated with poly-factorial pathogenic mechanisms, with several neurotransmitter systems closely involved. In addition to the cerebral dopaminergic (DA) system, the serotoninergic (5-HT) system also plays a crucial role in regulating psychoemotional, cognitive and motor functions in the central nervous system (CNS). Among the large 5-HT receptor family, accumulating data have revealed new insights into the therapeutic benefit of the 5-HT1A receptor in treating various CNS disorders, especially schizophrenia and Parkinson's disease. The present review discusses the advance of dual agents with mixed actions at the dopamine D2 and serotonin 5-HT1A receptors in the treatment of these diseases. Aripiprazole was the only marketed drug with dual D2 and 5-HT 1A profile. It is a partial D2 and 5-HT1A receptor agonist and has been prescribed as an atypical antipsychotical drug. Two other drugs Cariprazine and Pardoprunox are being investigated in clinic. Most of the other candidate compounds, including Bifeprunox, Sarizotan, Mazapertine succinate, PF-217830, and Adoprazine were discontinued due to either non-optimal pharmacokinetic properties or insufficient therapeutical efficacy. Although much effort has been done to highlight the advantages of the 5-HT 1A and D2 dual approach, it has to be pointed out that many of these drugs showed poly-pharmacological profile by targeting many other receptors and/or transporters besides the D2 and 5-HT1A receptors. In this regard, 'pure' compounds exclusively acting on the D 2 and 5-HT1A receptors are highly needed to further validate this approach. Meanwhile, safety concerns and in vivo pharmacokinetic alerts should also be implanted to the drug design art early.

AB - Psychiatric disorders like schizophrenia and neurodegenerative diseases like Parkinson's disease are associated with poly-factorial pathogenic mechanisms, with several neurotransmitter systems closely involved. In addition to the cerebral dopaminergic (DA) system, the serotoninergic (5-HT) system also plays a crucial role in regulating psychoemotional, cognitive and motor functions in the central nervous system (CNS). Among the large 5-HT receptor family, accumulating data have revealed new insights into the therapeutic benefit of the 5-HT1A receptor in treating various CNS disorders, especially schizophrenia and Parkinson's disease. The present review discusses the advance of dual agents with mixed actions at the dopamine D2 and serotonin 5-HT1A receptors in the treatment of these diseases. Aripiprazole was the only marketed drug with dual D2 and 5-HT 1A profile. It is a partial D2 and 5-HT1A receptor agonist and has been prescribed as an atypical antipsychotical drug. Two other drugs Cariprazine and Pardoprunox are being investigated in clinic. Most of the other candidate compounds, including Bifeprunox, Sarizotan, Mazapertine succinate, PF-217830, and Adoprazine were discontinued due to either non-optimal pharmacokinetic properties or insufficient therapeutical efficacy. Although much effort has been done to highlight the advantages of the 5-HT 1A and D2 dual approach, it has to be pointed out that many of these drugs showed poly-pharmacological profile by targeting many other receptors and/or transporters besides the D2 and 5-HT1A receptors. In this regard, 'pure' compounds exclusively acting on the D 2 and 5-HT1A receptors are highly needed to further validate this approach. Meanwhile, safety concerns and in vivo pharmacokinetic alerts should also be implanted to the drug design art early.

KW - Atypical antipsychotics

KW - Dopamine D receptor

KW - Dual ligands

KW - Parkinson's disease

KW - Schizophrenia

KW - Serotonin 5-HT receptor

UR - http://www.scopus.com/inward/record.url?scp=84893304140&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84893304140&partnerID=8YFLogxK

U2 - 10.2174/09298673113206660300

DO - 10.2174/09298673113206660300

M3 - Article

VL - 21

SP - 437

EP - 457

JO - Current Medicinal Chemistry

JF - Current Medicinal Chemistry

SN - 0929-8673

IS - 4

ER -