Recent Developments in Studies of l-Stepholidine and its Analogs: Chemistry, Pharmacology and Clinical Implications

Abstract

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.

Conditioned Avoidance Response in the Development of New Antipsychotics

“…Treatment with l-stepholidine alone also showed therapeutic effect, a reduction in negative symptoms, and a safe EPS liability profile [126].…”

(-)-Stepholidine is a potent pan-dopamine receptor antagonist of both G protein- and β-arrestin-mediated signaling

“…(−)-Stepholidine is a tetrahydroberberine alkaloid, originally isolated from the Chinese herb Stephania intermedia , which has been used in traditional Chinese medicine to treat various maladies (Mo et al 2007; Yang et al 2007). The effects of (−)-stepholidine on regulating various dopaminergic systems involved in the treatment of disease have also been examined.…”

“…The effects of (−)-stepholidine on regulating various dopaminergic systems involved in the treatment of disease have also been examined. (−)-Stepholidine has been purported to display a variety of therapeutic actions including enhancing the effects of typical antipsychotics, and improvement of antipsychotic-induced dyskinesias (Mo et al 2007). Furthermore, it has been reported that (−)-stepholidine relieves motor symptoms of Parkinson’s disease when co-administered with L-DOPA (Yang et al 2007) or bromocriptine (Jin et al 2002), and may slow the progression of neuronal degeneration in Parkinson’s patients (Yang et al 2007).…”

“…With respect to the actions of (−)-stepholidine on specific dopamine receptor subtypes, all evidence to date suggests that it is an antagonist of D2-like receptors, however, since most studies were performed using behavioral outputs or ex vivo tissue assays, the effects on individual receptor subtypes could not be determined (Jin et al 2002; Mo et al 2007; Yang et al 2007). The actions of (−)-stepholidine on D1-like receptors have been significantly more controversial and difficult to discern.…”

Dopamine D1receptor and serotonin 5-HT1Areceptor agonist effects of the natural product (–)-stepholidine: molecular modelling and dynamics simulations

“…l-Stepholidine (l-SPD), which is extracted from the Chinese herb Stephania, is a dihydroxytetrahydroprotoberberine that displays the high affinity in its class for D 1 -and 5-HT 1A -like receptors [3,4]. l-SPD, because of its specific pharmacological dual action on D 1 and 5-HT 1A , is a potential novel antipsychotic drug not inducing any effects of extrapyramidal system (EPS) [5].…”