stepholidine and berbine

The tetrahydroprotoberberines (THPBs) are compounds isolated from Chinese herbs that possess a unique pharmacological profile as D2 dopamine receptor antagonists and D1 receptor agonists. l-Tetrahydropalmatine (l-THP) and l-stepholidine (SPD), members of the THPB family, were shown to have potential clinical use in the treatment of pain. However, their mechanism of action is not clear. In the past decades, Chinese scientists have made a great deal of effort to explore the mechanisms by which the THPBs and its analogues elicit antinociception and their potential utility in treating drug abuse. It is now clear that the antinociception produced by l-THP is related to inhibition of D(2) dopamine receptors. The present review focuses on the recent progress made in understanding the mechanisms of l-THP- and l-SPD-mediated antinociception and the sequel of drug addiction.

Topics: Analgesics; Animals; Berberine; Berberine Alkaloids; Dopamine Antagonists; Humans; Models, Biological; Pain; Receptors, Dopamine; Substance-Related Disorders

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.

Topics: Berberine; Berberine Alkaloids; Dopamine; Humans; Mental Disorders; Parkinson Disease; Receptors, Dopamine

A novel series of tetrahydroprotoberberine derivatives (THPBs) were designed, synthesized, and evaluated as selective α

Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Berberine Alkaloids; Dose-Response Relationship, Drug; Drug Design; Ether-A-Go-Go Potassium Channels; HEK293 Cells; Humans; Male; Mice; Mice, Inbred Strains; Molecular Structure; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-1; Structure-Activity Relationship; Tumor Cells, Cultured

To discover new inhibitors on tissue factor procoagulant activity, 21 tetrahydroprotoberberines were screened on the model of human THP-1 cells stimulated by lipopolysaccharide. Among these tetrahydroprotoberberines, several unique compounds were synthesized through microbial transformation: compound 6 (l-corydalmine) was obtained through regio-selective demethylation by Streptomyces griseus ATCC 13273, whereas compounds 4a, 4b, 5h, and 5i were microbial glycosylation products by Gliocladium deliquescens NRRL1086. The bioassay results showed that compounds 3 (tetrahydroberberine), 10 (tetrahydroberberrubine), and 5f (cinnamyl ester of 5) and 5i (glycosidic product of 5), exhibited the most potential effects, with IC(50) values of 8.35, 6.75, 3.75, and 8.79 nM, respectively. The preliminary structure and activity relationship analysis revealed that the 2,3-methylenedioxy group of the A ring was essential for the strong inhibitory effects, and the R configuration of the chiral center C-14 showed higher activity than S-form products. The formation of fatty acid or aromatic acid esters of compound 5, except the cinnamyl esters, would weaken its effects. It is also interesting to note that the glycosylation of tetrahydroprotoberberines will maintain and even enhance the inhibitory effects. Because of the importance of glycochemistry in new drug discovery and development, this deserves further exploration and may provide some guide on the semi-synthesis of tetrahydroprotoberberines as tissue factor pathway inhibitors. Our findings also provide some potential leading compounds for tissue factor-related diseases, such as cancer and cardiovascular diseases.

Topics: Berberine Alkaloids; Cell Line; Gliocladium; Glycosylation; Humans; Streptomyces griseus; Structure-Activity Relationship; Thromboplastin

A series of new tetrahydroprotoberberine (THPB) derivatives were designed, synthesized, and tested for their binding affinity towards dopamine (D(1) and D(2)) and serotonin (5-HT(1A) and 5-HT(2A)) receptors. Many of the THPB compounds exhibited high binding affinity and activity at the dopamine D(1) receptor, as well as high selectivity for the D(1) receptor over the D(2), 5-HT(1A), and 5-HT(2A) receptors. Among these, compound 19c exhibited a promising D(1) receptor binding affinity (K(i)=2.53nM) and remarkable selectivity versus D(2)R (inhibition=81.87%), 5-HT(1A)R (inhibition=61.70%), and 5-HT(2A)R (inhibition=24.96%). Compared with l-(S)-stepholidine (l-SPD) (D(1)K(i)=6.23nM, D(2)K(i)=56.17nM), compound 19c showed better binding affinity for the D(1) receptor (2.5-fold higher) and excellent D(2)/D(1) selectivity. Functional assays found compounds 18j, 18k, and 19c are pure D(1) receptor antagonists. These results indicate that removing the C10 hydroxy group and introducing a methoxy group at C11 of the pharmacophore of l-SPD can reverse the function of THPB compounds at the D(1) receptor. These results are in accord with molecular docking studies.

Topics: Berberine Alkaloids; Dose-Response Relationship, Drug; Drug Design; HEK293 Cells; Humans; Models, Molecular; Molecular Structure; Receptors, Dopamine D1; Structure-Activity Relationship

To study the effects of tetrahydroprotoberberines (THPB) on rat liver and brain lipid peroxidation (LPO) and oxygen free radicals generation.. The malondialdehyde (MDA) levels in rat brain and liver homogenates, induction of MDA by Fe(2+)-Vit C in mitochondria, OH. generation by Fenton reaction, and O2.- generation by pyrogallol oxidation were observed in vitro.. (1) THPB lowered the MDA contents in the liver homogenate and mitochondria, and the IC50 values of l-THPB-18 and l-stepholidine (SPD) in the liver mitochondria were 3.1 and 12.7 mumol.L-1 respectively. SPD decreased the MDA contents in the brain homogenate and mitochondria with IC50 values of 102 and 35.0 mumol.L-1 respectively. (2) THPB scavenged OH., and the IC50 values of l-THPB-18 and SPD were 0.21 and 3.8 mumol.L-1 respectively, but no effect on O2.- was observed.. THPB could reduce the MDA contents and scavenge OH. and THPB-18 was the most potent amongst them.

Topics: Animals; Antioxidants; Berberine; Berberine Alkaloids; Brain; Free Radical Scavengers; Hydroxyl Radical; Lipid Peroxidation; Liver; Male; Malondialdehyde; Rats; Rats, Sprague-Dawley

To study the effect of tetrahydropalmatine (THP) analogs on Fos protein expression induced by formalin-pain and elucidate analgesic mechanism of THP analogs.. The pain response to Sprague Dawley rats was induced with formalin injected s.c. into the plantar surface of the right hindpaw. Fos protein expression in brain and spinal cord was investigated with immunohistochemistry. The numbers of Fos-like immunoreactive (FLI) neurons were counted with Leica Q570 image analyzer.. In the groups of THP analogs and D2 antagonist spiperone, FLI neurons induced by intraperitoneal (i.p.) injection of THP analogs and spiperone were mainly located in the striatum and accumbens nucleus, and a few FLI neurons were also in sensorimotor cortex. In the D1 antagonist, D1 agonist, D2 agonist, saline and vehicle groups, FLI neurons were seldom seen in the striatum and accumbens nucleus. Moreover, the Fos protein expression induced by l-THP and spiperone could be prevented by the pre-treatment of the D2 agonist quinpirole but not D1 agonist SKF38393. In the formalin-pain group, FLI neurons were mainly distributed in ascending pain afferent system (APAS) and descending pain modulation system (DPMS). Following i.p. THP analogs, however, the numbers of FLI neurons induced by formalin-pain in the APAS, such as dorsal horn (mainly laminae I, II, IV-VI) were markedly decreased, while the numbers of FLI neurons in the DPMS, such as periaqueductal gray (PAG) and reticular paragigantocellular lateral nucleus (RPLN) were significantly increased.. THP analogs enhanced the activity of brainstem DPMS by the blockade of D2 receptors in the striatum and accumbens nucleus, and sequentially inhibited the inputs of peripheral pain afferent message in spinal cord level.

Topics: Analgesics, Non-Narcotic; Animals; Berberine; Berberine Alkaloids; Brain; Dopamine Agonists; Dopamine Antagonists; Formaldehyde; Male; Pain; Proto-Oncogene Proteins c-fos; Quinpirole; Rats; Rats, Sprague-Dawley; Spinal Cord; Spiperone

To build up the structure models of dopamine receptors, then combined with the receptor models, to investigate the action mechanism of tetrahydroprotoberberines (THPB) on dopamine receptors at the molecular level.. Using the three-dimensional structure of bacteriorhodopsin as a template, we have constructed dopamine D1 and D2 receptor models on computer. l-Stepholidine was selected as the leading compound of THPB and docked into D1 and D2 receptor active sites.. After manual adjustment and energy minimization, the ligand-receptor interaction models were achieved. Based on these models, the possible action mechanism of THPB on dopamine receptors was suggested that the protonated N atom of THPB form electrostatic interaction and hydrogen-bonding interaction with residue Asp in TM3 of the receptor, the two substituents in D ring of THPB form hydrogen-bonding interactions with two Ser residues in TM5 of the receptor, and the aryl groups form pi-pi interactions with some aryl residues of the receptor around ligand.. Our ligand-receptor interaction models should be helpful for rational design of more potent drugs.

Topics: Amino Acid Sequence; Bacteriorhodopsins; Berberine; Berberine Alkaloids; Binding Sites; Dopamine Antagonists; Drug Interactions; Models, Chemical; Molecular Sequence Data; Receptors, Dopamine D1; Receptors, Dopamine D2

Topics: Animals; Berberine; Berberine Alkaloids; Dopamine Antagonists; Drugs, Chinese Herbal; Stereoisomerism; Structure-Activity Relationship

The effects of 12 tetrahydroprotoberberines (THPBs) on D1 and D2 receptors labelled with [3H]DA, [3H]Sch-23390 and [3H]spiperone were evaluated. Their effects on the activity of adenylate cyclase stimulated with DA 40 mumols/L were also assessed. All of the l-THPBs tested behaved as DA receptor antagonists with preferential affinity toward the D1 receptors. Among them, l-stepholidine (l-SPD), a THPB analog with 2 hydroxy groups at the C2 and C10 positions, was the most potent. Its affinity toward D1 receptors was 4-7 times higher than that toward D2 receptors. The results suggest that the hydroxy groups in l-THPBs are very important factors in determining the affinity to DA receptors. Moreover, d-tetrahydropalmatine (d-THP), a dextro-THPB analog, displayed no affinity for the D2 receptor subtype, while its optical isomer, l-THP, was a DA receptor antagonist. This indicates that the levo-optical configuration is necessary for the affinity of THPBs to DA receptors. In addition, l-SPD was 18 times more potent than haloperidol with respect to binding to D1 receptors, but 14 times weaker for D2 receptors. Thus, it is expected that the clinical effects of l-SPD can be distinguished from that of haloperidol.

Topics: Adenylyl Cyclases; Alkaloids; Animals; Berberine; Berberine Alkaloids; Brain; Cattle; Corpus Striatum; Rats; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Stereoisomerism

In rats lesioned by unilateral micro-injection of 6-OHDA into substantia nigra, the apomorphine-induced contralateral rotation and the amphetamine-induced ipsilateral rotation were antagonized by THB, l-THP and haloperidol. Scopolamine reversed the antagonistic effect of THB against amphetamine. Thus, THB and l-THP exhibited the DA-receptor antagonistic property which was similar to that of haloperidol. l-SPD (10 mg/kg), however, only antagonized the amphetamine-challenged rotational response, while it could not antagonize, but potentiate, the apomorphine-challenged rotational response. So, l-SPD might be a partial agonistic antagonist of DA-receptors, and its effect was more potent than that of THB and l-THP. l-SPD would be ascertained further in clinic trial. From these results and others, the authors suggest that THPB is a new chemical type of antagonist of brain DA-receptors.

Topics: Alkaloids; Animals; Antipsychotic Agents; Berberine; Berberine Alkaloids; Corpus Striatum; Haloperidol; Rats; Receptors, Dopamine; Scopolamine; Substantia Nigra