Tetrahydroprotoberberines (THPBs) represent a series of compounds extracted from the Chinese herb Corydalis ambigua and various species of Stephania. THPBs, dependent on the presence of
hydroxyl groups in its structure, are divided into three types: nonhydroxyl-THPBs, monohydroxyl-THPBs and dihydroxyl-THPBs. THPBs are identified as a new category of
dopamine receptor ligands. Among all THPBs, dihydroxyl-THPBs attracted particular attention because of their dual actions on
dopamine (DA) receptors. They exhibit D(1) receptor agonistic activity while acting as D(2) receptor antagonists. This unique pharmacological profile made dihydroxyl-THPBs such as
l-stepholidine (l-SPD) potential agents in the treatment of
drug addiction,
Parkinson's disease, and especially,
schizophrenia. Clinical studies have shown that co-administration of l-SPD with a typical
antipsychotic drug significantly enhances the
therapeutic effects and remarkably reduces the
tardive dyskinesia induced by the typical
antipsychotic drug used with schizophrenic patients. Moreover, l-SPD alone was shown to have therapeutic value without inducing significant extrapyramidal side effects and also seemed to reduce the negative symptoms of
schizophrenia. This is confirmed in experimental studies using animal models of
schizophrenia, in which l-SPD improved social interaction and cognitive function, inhibited hyperactivity in schizophrenic animals. This review discusses the chemistry, pharmacology and clinical implications of l-THPBs in the
drug development for
psychosis and neurobiological diseases.