HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Asymmetric total synthesis and identification of tetrahydroprotoberberine derivatives as new antipsychotic agents possessing a dopamine D(1), D(2) and serotonin 5-HT(1A) multi-action profile.

Abstract
An effective and rapid method for the microwave-assisted preparation of the key intermediate for the total synthesis of tetrahydroprotoberberines (THPBs) including l-stepholidine (l-SPD) was developed. Thirty-one THPB derivatives with diverse substituents on A and D ring were synthesized, and their binding affinity to dopamine D(1), D(2) and serotonin 5-HT(1A) and 5-HT(2A) receptors were determined. Compounds 18k and 18m were identified as partial agonists at the D(1) receptor with K(i) values of 50 and 6.3nM, while both compounds act as D(2) receptor antagonists (K(i)=305 and 145nM, respectively) and 5-HT(1A) receptor full agonists (K(i)=149 and 908nM, respectively). These two THPBs compounds exerted antipsychotic actions in animal models. Further electrophysiological studies employing single-unit recording in intact animals demonstrated that 18k-excited dopaminergic (DA) neurons are associated with its 5-HT(1A) receptor agonistic activity. These results suggest that these two compounds targeted to multiple neurotransmitter receptors may present novel lead drugs with new pharmacological profiles for the treatment of schizophrenia.
AuthorsHaifeng Sun, Liyuan Zhu, Huicui Yang, Wangke Qian, Lin Guo, Shengbin Zhou, Bo Gao, Zeng Li, Yu Zhou, Hualiang Jiang, Kaixian Chen, Xuechu Zhen, Hong Liu
JournalBioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 21 Issue 4 Pg. 856-68 (Feb 15 2013) ISSN: 1464-3391 [Electronic] England
PMID23332346 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 Elsevier Ltd. All rights reserved.
Chemical References
  • Antipsychotic Agents
  • Berberine Alkaloids
  • Dopamine D2 Receptor Antagonists
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • Serotonin 5-HT1 Receptor Agonists
  • Berberine
  • stepholidine
  • Receptor, Serotonin, 5-HT1A
  • protoberberine
Topics
  • Animals
  • Antipsychotic Agents (chemical synthesis, pharmacology, therapeutic use)
  • Berberine (analogs & derivatives, chemistry)
  • Berberine Alkaloids (chemical synthesis, chemistry)
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Dopamine D2 Receptor Antagonists
  • HEK293 Cells
  • Humans
  • Microwaves
  • Motor Activity (drug effects)
  • Protein Binding
  • Rats
  • Receptor, Serotonin, 5-HT1A (chemistry, metabolism)
  • Receptor, Serotonin, 5-HT2A (chemistry, metabolism)
  • Receptors, Dopamine D1 (antagonists & inhibitors, metabolism)
  • Receptors, Dopamine D2 (metabolism)
  • Schizophrenia (chemically induced, drug therapy)
  • Serotonin 5-HT1 Receptor Agonists (chemistry, pharmacology, therapeutic use)
  • Structure-Activity Relationship

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: