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Design, synthesis, and pharmacological evaluation of novel tetrahydroprotoberberine derivatives: Selective inhibitors of dopamine D1 receptor
- Source :
-
Bioorganic & Medicinal Chemistry . Aug2012, Vol. 20 Issue 15, p4862-4871. 10p. - Publication Year :
- 2012
-
Abstract
- Abstract: A series of new tetrahydroprotoberberine (THPB) derivatives were designed, synthesized, and tested for their binding affinity towards dopamine (D1 and D2) and serotonin (5-HT1A and 5-HT2A) 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-HT1A, and 5-HT2A receptors. Among these, compound 19c exhibited a promising D1 receptor binding affinity (K i =2.53nM) 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 K i =6.23nM, D2 K i =56.17nM), 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. [Copyright &y& Elsevier]
Details
- Language :
- English
- ISSN :
- 09680896
- Volume :
- 20
- Issue :
- 15
- Database :
- Academic Search Index
- Journal :
- Bioorganic & Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 78036753
- Full Text :
- https://doi.org/10.1016/j.bmc.2012.05.057