Design, synthesis, and pharmacological evaluation of novel tetrahydroprotoberberine derivatives: Selective inhibitors of dopamine D1 receptor

Qian, Wenyuan; Lu, Weijian; Sun, Haifeng; Zeng, Li; Zhu, Liyuan; Zhao, Rui; Zhang, Lei; Zhou, Shengbin; Zhou, Yu; Jiang, Hualiang; Zhen, Xuechu; Liu, Hong

doi:10.1016/j.bmc.2012.05.057

Cited by 26 publications

(19 citation statements)

References 36 publications

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“…Naturally occurring THPBs as well as synthetic derivatives have shown activity at D1 and D2 receptors and are promising lead compounds for the development of therapeutics to treat a range of neuropsychiatric disorders and drug abuse. 1, 2 For example, stepholidine ( 1, Figure 1) displays a very rare D1 agonist/D2 antagonist/D3 antagonist profile and possesses antipsychotic, memory enhancing and anti-addiction properties. 3-12 Isocorypalmine ( 2 ) is a D1 partial agonist/D2 antagonist/D3 antagonist that has been shown to reduce cocaine reinstatement.…”

Section: Introductionmentioning

confidence: 99%

“…1, 2, 28-30 We considered the possibility that the THPB scaffold could provide a source for novel compounds with potent polypharmacological activities at dopamine receptors. We are particularly interested in obtaining compounds that possess selective, dual D1/D3 activity (but lacking D2 affinity) as such compounds will be useful as tools to further probe the effects of multiple receptor modulation in the treatment of substance abuse disorders.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and evaluation of C9 alkoxy analogues of (-)-stepholidine as dopamine receptor ligands

Madapa

Gadhiya

Kurtzman

et al. 2017

European Journal of Medicinal Chemistry

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of C9 alkoxy analogues of (-)-stepholidine as dopamine receptor ligands

Madapa

Gadhiya

Kurtzman

et al. 2017

European Journal of Medicinal Chemistry

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“…Moreover, in comparison with SCH23390 (IC 50 = 0.52 μ m ), (−)‐ 15e (IC 50 = 0.14 μ m ) showed comparable or even higher antagonistic activities for D1R. According to the work depicted by Qian et al . removal of C10 hydroxy group and introduction of a methoxy group at C11 of the pharmacophore of l ‐SPD can reverse the function of THPB s at the D1 receptor (Figure ), resulting in the antagonistic activities against D1R.…”

Section: Discussionmentioning

confidence: 88%

Functional reversal of (−)‐Stepholidine analogues by replacement of benzazepine substructure using the ring‐expansion strategy

Zhang

et al. 2016

Chem Biol Drug Des

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(-)-Stepholidine is an active ingredient of the Chinese herb Stephania and naturally occurring tetrahydroprotoberberine alkaloid with mixed dopamine receptor D1 agonistic and dopamine receptor D2 antagonistic activities. In this work, a series of novel hexahydrobenzo[4,5]azepino [2,1-a]isoquinolines were designed and synthesized as ring-expanded analogues of (-)-Stepholidine. Initial pharmacological assays demonstrated that a benzazepine replacement was associated with significant increase in selectivity and functional reversal at dopamine receptor D1 . Compound-(-)-15e (Ki = 5.32 ± 0.01 nm) is more potent than (-)-Stepholidine (Ki = 13 nm) and was identified as a selective dopamine receptor D1 antagonist (IC50 = 0.14 μm). Moreover, molecular modeling suggested that (-)-15e might exert its dopamine receptor D1 antagonistic activities through interacting with the transmembrane helix 7 of dopamine receptor D1 .

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“…This result is in accordance with observations from previous SAR work on the THPB framework by others. 32,31 Methyl and ethyl substituents resulted in an approximately 2-fold decrease in affinity (compounds 10 and 11 respectively). In the n -propyl ( 12 ) to n -hexyl ( 15 ) homologous series, a progressive decrease in affinity was observed.…”

Section: Resultsmentioning

confidence: 99%

“…31,32 The antipsychotic and anti-drug abuse potential of (−)-stepholidine has been attributed to its unusual D1 agonist/D2 antagonist profile. (−)-Stepholidine also shows good affinity for σ2 (K i = 54 nM) and D3 receptors (K i = 30 nM), as revealed by data from the Psychoactive Drug Screening Program (PDSP) database.…”

Section: Introductionmentioning

confidence: 99%

Tetrahydroprotoberberine alkaloids with dopamine and σ receptor affinity

Gadhiya

Madapa

Kurtzman

et al. 2016

Bioorganic & Medicinal Chemistry

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Two series of analogues of the tetrahydroprotoberberine (THPB) alkaloid (±)-stepholidine that a) contain various alkoxy substituents at the C10 position and, b) were de-rigidified with respect to (±)-stepholidine, were synthesized and evaluated for affinity at dopamine and σ receptors in order to evaluate effects on D3 and σ2 receptor affinity and selectivity. Small n-alkoxy groups are best tolerated by D3 and σ2 receptors. Among all compounds tested, C10 methoxy and ethoxy analogues (10 and 11 respectively) displayed the highest affinity for σ2 receptors as well as σ2 versus σ1 selectivity and also showed the highest D3 receptor affinity. De-rigidification of stepholidine resulted in decreased affinity at all receptors evaluated; thus the tetracyclic THPB framework is advantageous for affinity at dopamine and σ receptors. Docking of the C10 analogues at the D3 receptor, suggest that an ionic interaction between the protonated nitrogen atom and Asp110, a H-bond interaction between the C2 phenol and Ser192, a H-bond interaction between the C10 phenol and Cys181 as well as hydrophobic interactions of the aryl rings to Phe106 and Phe345, are critical for high affinity of the compounds.

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Design, synthesis, and pharmacological evaluation of novel tetrahydroprotoberberine derivatives: Selective inhibitors of dopamine D1 receptor

Cited by 26 publications

References 36 publications

Synthesis and evaluation of C9 alkoxy analogues of (-)-stepholidine as dopamine receptor ligands

Synthesis and evaluation of C9 alkoxy analogues of (-)-stepholidine as dopamine receptor ligands

Functional reversal of (−)‐Stepholidine analogues by replacement of benzazepine substructure using the ring‐expansion strategy

Tetrahydroprotoberberine alkaloids with dopamine and σ receptor affinity

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