title: 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.
authors: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
authors: Haifeng
authors: H
authors: Sun
authors: Liyuan
authors: L
authors: Zhu
authors: Huicui
authors: H
authors: Yang
authors: Wangke
authors: W
authors: Qian
authors: Lin
authors: L
authors: Guo
authors: Shengbin
authors: S
authors: Zhou
authors: Bo
authors: B
authors: Gao
authors: Zeng
authors: Z
authors: Li
authors: Yu
authors: Y
authors: Zhou
authors: Hualiang
authors: H
authors: Jiang
authors: Kaixian
authors: K
authors: Chen
authors: Xuechu
authors: X
authors: Zhen
authors: Hong
authors: H
authors: Liu
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001599:Berberine / Q000031:analogs & derivatives / Q000737:chemistry; D001600:Berberine Alkaloids / Q000138:chemical synthesis / Q000737:chemistry*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D065127:Dopamine D2 Receptor Antagonists; D057809:HEK293 Cells; D006801:Humans; D008872:Microwaves; D009043:Motor Activity / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry* / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012559:Schizophrenia / Q000139:chemically induced / Q000188:drug therapy; D058825:Serotonin 5-HT1 Receptor Agonists / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D001600:Berberine Alkaloids; D065127:Dopamine D2 Receptor Antagonists; D044402:Receptor, Serotonin, 5-HT2A; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D058825:Serotonin 5-HT1 Receptor Agonists; D001599:Berberine; C010513:stepholidine; D044282:Receptor, Serotonin, 5-HT1A; C009090:protoberberine