Rotundine

Levo-tetrahydropalmatine (l-THP) is an active herbal constituent of preparations containing plant species of the genera Stephania and Corydalis. In China, it has been approved and used for a number of clinical indications under the drug name Rotundine.

In vitro: In contrast to other THPB derivatives, l-THP is an antagonist at both of D1 and D2 receptors. The Ki values for l-THP at D1 and D2 dopamine receptors are approximately 124 nM (D1) and 388 nM (D2), while the IC50 values are 166 nM and 1.4 μM for D1 and D2, respectively. The relatively high affinity of l-THP at D1 vs. D2 receptors, distinguishes it from other available dopamine receptor antagonist drugs (e.g., haloperidol) [1].

In vivo: It has been found that l-THP produces dose-dependent reductions in locomotor activity and operant responding for non-drug reinforcers in rats [1].

Clinical trials: It has long been recognized l-THP has therapeutic values for treating a number of CNS related conditions. The effectiveness of l-THP as a non-opioid analgesic agent resulted in the approval of purified l-THP for this indication by the Chinese SFDA and has led to extensive investigation of the pharmacological properties of l-THP [1]

Reference:
[1] Wang JB, Mantsch JR.   l-tetrahydropalamatine: a potential new medication for the treatment of cocaine addiction. Future Med Chem. 2012 Feb;4(2):177-86.

[Enhancing effect of volatile oils of rhizoma zingiberis, flos magnoliae and fructus litseae on permeation of rotundine in vitro].[Pubmed:21954565]

Zhong Yao Cai. 2011 May;34(5):753-7.

OBJECTIVE: To investigate the enhancing effect of volatile oils of Rhizoma Zingiberis (RZ), Flos Magnoliae (FM), Fructus Litseae (FL), Azone and pairwise combinations on the permeation of Rotundine in vitro. METHODS: To screen out the volatile oils with the best percutaneous enhancing effect on Rotundine, a test of penetration through rats skin was conducted by using an improved Franz diffusion cell. The accumulative penetration amount of Rotundine was determined by UV and HPLC. RESULTS: All of the 3 volatile oils had enhancing effect on Rotundine permeation. The average accumulative doses of Rotundine for 8 hours (Q8, mg/cm2) of 5% volatile oil of FL, 5% volatile oil of, RZ, 2.5% FL + 2.5% Azone were 6.0758, 6.1148, 6.5487, the enhancement ratios of 4 hours were 1.01, 1.00, 1.13 respectively. CONCLUSION: 2.5% FL + 2.5% Azone had the best effect of percutaneous enhancing on Rotundine.

[Effects of rotundine injection on nitric oxide synthase in tissues of different organs after ischemia/reperfusion of brain in rats].[Pubmed:17577446]

Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2007 Jun;19(6):361-4.

OBJECTIVE: To explore the protective effect of Rotundine injection on lung, liver and kidney damages after cerebral ischemia/reperfusion (I/R) injury in rats based on the activity changes of nitric oxide synthase (NOS). METHODS: Seventy-six rats were randomly divided into three groups: sham operation group, I/R injury group and treatment group, and determinations were done at five different time points. The cerebral I/R models were reproduced by improved 4 vessels occlusion method. The activities of NOS in the lung, liver and kidney were measured in all the rats at 2, 6, 12, 24 and 48 hours after reperfusion. RESULTS: Compared with sham operation group, the activities of total NOS (tNOS) were significantly increased at 2, 12 and 24 hours in I/R injury group (P<0.05 or P<0.01), with the peak value at 12 hours (all P<0.01). The activities of constitutive NOS (cNOS) were increased significantly at 2 hours (all P<0.05), and those of induced NOS (iNOS) were increased at 12 hours (all P<0.01). The activities of iNOS were still high at 24 hours (all P<0.05), and approached the levels of sham operation group at 48 hours. Compared with I/R injury group, the activities of cNOS in various organs increased much higher at 2 hours in treatment group (all P<0.05). But those of iNOS were significantly decreased after 12 hours (P<0.05 or P<0.01). CONCLUSION: The various types of NOS play different roles in the lung damages after brain I/R injury at different stages in rats. Rotundine injection can ameliorate the damages by modulating the activities of different types of NOS.

[IR and Raman spectra studies of Rotundine based on DFT].[Pubmed:25752044]

Guang Pu Xue Yu Guang Pu Fen Xi. 2014 Nov;34(11):2989-93.

Infrared spectroscopy (IR), the normal Raman spectroscopy (NRS) and the surface enhanced Raman spectroscopy (SERS) in new Ag/Cu nanomaterial of Rotundine were studied in the present paper. The IR and the NRS of Rotundine were calculated by the density functional theory (DFT) using B3LYP/6-311+G(d, p), then the spectral intensity graph of Rotundine were given. The vibrational peaks were assigned comprehensively by the visualization software of Gauss view 5. 0. Rotundine has obvious infrared and Raman vibrational peak in the wave number range of 3 300-2500 and 1 800-600 cm(-1). SnCl2 and PVP was used as capping agent for the silver nanoparticles in SERS of Rotundine. Finally, by using the method of cyclic immersion well dispersed silver nanoparticles was obtained and achieved good enhancement effect. This molecule acquired strong selective enhancement vibration peak, In the wave number ranges of 1 500-1 400 and 1 000-700 cm(-1) the enhancement effect is most obvious. After analyzed, the methylene of this molecule is adsorbed on the silver nanoparticles surface and the angle between the benzene ring and the silver substrate is close to 90 degrees. The theoretically calculated spectra of Rotundine are consistent with the obtained experimental spectra. There are some differences may be due to the interaction forces between molecules and so on. The visualization software displayed the structure characteristics and molecular group vibration of this molecular visually and provided important basis for assigning the vibrational peaks. Rotundine is an important traditional Chinese medicine agent contained in many kinds of sedative drugs. The study provides a strong basis for the rapid, feature and trace identification of Rotundine and also supplies important reference for the biological role of central inhibition of analgesic drugs.

[In vitro O-demethylation of rotundine by recombinant human CYP isoenzymes].[Pubmed:21351505]

Yao Xue Xue Bao. 2010 Mar;45(3):307-13.

Rotundine (1 micromol L(-1)) was incubated with a panel of rCYP enzymes (1A2, 2C9, 2C19, 2D6 and 3A4) in vitro. The remained parent drug in incubates was quantitatively analyzed by an Agilent LC-MS. CYP2C19, 3A4 and 2D6 were identified to be the isoenzymes involved in the metabolism of Rotundine. The individual contributions of CYP2C19, 3A4 and 2D6 to the Rotundine metabolism were assessed using the method of total normalized rate to be 31.46%, 60.37% and 8.17%, respectively. The metabolites of Rotundine in incubates were screened with ESI-MS at selected ion mode, and were further identified using MS2 spectra and precise molecular mass obtained from an Agilent LC/Q-TOF-MSMS, as well as MS(n) spectra of LC-iTrap-MS(n). The predominant metabolic pathway of Rotundine in rCYP incubates was O-demethylation. A total 5 metabolites were identified including 4 isomerides of mono demethylated Rotundine and one di-demethylated metabolite. The results also showed that CYP2C19, 2D6 and 3A4 mediated O-demethylation of methoxyl groups at different positions of Rotundine. Furthermore, the ESI-MS cleavage patterns of Rotundine and its metabolites were explored by using LC/Q-TOF-MSMS and LC/iTrap-MS(n) techniques.