- Design, synthesis, and pharmacological evaluation of novel tetrahydroprotoberberine derivatives: Selective inhibitors of dopamine D 1 receptor
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A series of new tetrahydroprotoberberine (THPB) derivatives were designed, synthesized, and tested for their binding affinity towards dopamine (D 1 and D2) and serotonin (5-HT1A and 5-HT 2A) receptors. Many of the THPB compounds exhibited high binding affinity and activity at the dopamine D1 receptor, as well as high selectivity for the D1 receptor over the D2, 5-HT 1A, and 5-HT2A receptors. Among these, compound 19c exhibited a promising D1 receptor binding affinity (Ki = 2.53 nM) and remarkable selectivity versus D2R (inhibition = 81.87%), 5-HT1AR (inhibition = 61.70%), and 5-HT2AR (inhibition = 24.96%). Compared with l-(S)-stepholidine (l-SPD) (D1 Ki = 6.23 nM, D2 Ki = 56.17 nM), compound 19c showed better binding affinity for the D1 receptor (2.5-fold higher) and excellent D2/D1 selectivity. Functional assays found compounds 18j, 18k, and 19c are pure D1 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 D1 receptor. These results are in accord with molecular docking studies.
- Qian, Wangke,Lu, Weijian,Sun, Haifeng,Li, Zeng,Zhu, Liyuan,Zhao, Rui,Zhang, Lei,Zhou, Shengbin,Zhou, Yu,Jiang, Hualiang,Zhen, Xuechu,Liu, Hong
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p. 4862 - 4871
(2012/09/05)
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- 1,2,3,4-TETRAHYDROISOQUINOLINE DERIVATIVES HAVING EFFECTS OF PREVENTING AND TREATING DEGENERATIVE AND INFLAMMATORY DISEASES
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Provided are 7-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline derivatives and synthesis methods thereof. The compounds significantly inhibit the production of nitrogen monoxide (NO) and superoxide in an activated microglial cell and expressions of TNF-α, IL-1β inducive NO synthase and cyclooxygenase-2 genes. They also prevent NF-kB shift to a nucleus, decrease reactive oxygen species (ROS), inhibit expression of GTP cyclohydrolase I gene and over-production of tetrahydrobiopterin (BH4), and protect dopaminergic neurons from injury due to activated microglial cells. Consequently, the compounds are effective in treating inflammatory and neurodegenerative diseases.
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Page/Page column 6
(2010/09/05)
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- 1,2,3,4-TETRAHYDROISOQUINOLINE DERIVATIVES HAVING EFFECTS OF PREVENTING AND TREATING DEGENERATIVE AND INFLAMMATORY DISEASES
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Provided are 7-hydroxy-6-methoxy-l,2,3,4-tetrahydroisoquinoline derivatives and synthesis methods thereof. The compounds significantly inhibit the production of nitrogen monoxide (NO) and superoxide in an activated microglial cell and expressions of TNF-α, IL- lβ inducive NO synthase and cyclooxygenase-2 genes. They also prevent NF-kB shift to a nucleus, decrease reactive oxygen species (ROS), inhibit expression of GTP cyclohydrolase I gene and over-production of tetrahydrobiopterin (BH 4 ), and protect dopaminergic neurons from injury due to activated microglial cells. Consequently, the compounds are effective in treating inflammatory and neurodegenerative diseases.
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- Incorporation of phenethylisoquinolines into colchicine in isolated seeds of Colchicum autumnale
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The physiological parameters for application experiments using immature seeds of Colchicum autumnale were optimized, so that incorporation rates in the range of 10% and higher were consistently obtained with intermediate precursors. Application of tritium and 13C-labelled phenethylisoquinolines showed that N-methylation occurs prior to the substitution of ring C and that the free hydroxy group in position 13 of autumnaline is necessary for the phenolic coupling reaction. Autumnaline gives rise to a vast array of metabolites in seeds of this plant.
- Nasreen, Amber,Gundlach, Heidrun,Zenk, Meinhart H.
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p. 107 - 115
(2007/10/03)
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