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.

Article Details

Citation

Copy to clipboard

Sun H, Zhu L, Yang H, Qian W, Guo L, Zhou S, Gao B, Li Z, Zhou Y, Jiang H, Chen K, Zhen X, Liu H

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.

Bioorg Med Chem. 2013 Feb 15;21(4):856-68. doi: 10.1016/j.bmc.2012.12.016. Epub 2012 Dec 21.

PubMed ID

23332346 [ View in PubMed

]

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Haloperidol	Dopamine D2 receptor	IC 50 (nM)	550	N/A	N/A	Details