Synthesis, Pharmacological Characterization, and Binding Mode Analysis of 8-Hydroxy-Tetrahydroisoquinolines as 5-HT7 Receptor Inverse Agonists.

IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
ACS Chemical Neuroscience Pub Date : 2025-02-05 Epub Date: 2025-01-21 DOI:10.1021/acschemneuro.4c00667
Camilla B Chan, Eline Pottie, Icaro A Simon, Adrian G Rossebø, Matthias M Herth, Kasper Harpsøe, Jesper L Kristensen, Christophe P Stove, Christian B M Poulie
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引用次数: 0

Abstract

The serotonin 7 receptor (5-HT7R) regulates various processes in the central nervous system, including mood, learning, and circadian rhythm control, among others. Receptor activation can lead to activation of the Gαs protein and a subsequent increase of intracellular cyclic adenosine monophosphate (cAMP). Receptor interaction with inverse agonists results in a decrease of basal cAMP levels and therefore a downstream effect of reduced neuronal excitability and neurotransmission. Recently, pellotine (1a), a Lophophora alkaloid, was unexpectedly shown to be an inverse agonist of the 5-HT7R. Therefore, we evaluated close analogs of compound 1a, both naturally occurring and synthetic analogs, as inverse agonists of the 5-HT7R. Functional evaluation in a GloSensor cAMP assay revealed a preference for an 8-hydroxy-6,7-dimethoxy substitution pattern over 6,7,8-trimethoxy analogs or 8-hydroxy-6,7-methylenedioxy analogs. This was supported by molecular dynamics simulations, where the 8-hydroxy substitution allowed more robust interaction with the 5-HT7R, which correlated with inverse agonism efficacy. Additionally, N-methylation (as in 1a) improved the potency of the evaluated analogs. In this series, the most potent inverse agonist was anhalidine (1b) (EC50 = 219 nM, Emax = -95.4%), which lacks the 1-methyl, compared to pellotine (1a), and showed a 2-fold higher functional potency. Altogether, these results provide key insights for the further development of potent low molecular weight inverse agonists of the 5-HT7R.

8-羟基-四氢异喹啉类5-HT7受体拮抗剂的合成、药理表征及结合模式分析
5-羟色胺7受体(5-HT7R)调节中枢神经系统的各种过程,包括情绪、学习和昼夜节律控制等。受体激活可导致Gαs蛋白的激活和细胞内环磷酸腺苷(cAMP)的增加。受体与反向激动剂的相互作用导致基础cAMP水平降低,从而导致神经元兴奋性和神经传递降低的下游效应。最近,一种lophophhora生物碱pellotine (1a)意外地被证明是5-HT7R的逆激动剂。因此,我们评估了化合物1a的接近类似物,包括天然存在的和合成的类似物,作为5-HT7R的逆激动剂。GloSensor cAMP分析的功能评估显示,8-羟基-6,7-二甲氧基取代模式优于6,7,8-三甲氧基类似物或8-羟基-6,7-亚二氧基类似物。分子动力学模拟支持了这一点,其中8-羟基取代允许与5-HT7R更强的相互作用,这与逆激动效应相关。此外,n -甲基化(如1a)提高了评估的类似物的效力。在这个系列中,最有效的逆激动剂是抗卤胺(1b) (EC50 = 219 nM, Emax = -95.4%),与pellotine (1a)相比,它缺乏1-甲基,并且显示出高2倍的功能效价。总之,这些结果为进一步开发有效的5-HT7R低分子量逆激动剂提供了关键见解。
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来源期刊
ACS Chemical Neuroscience
ACS Chemical Neuroscience BIOCHEMISTRY & MOLECULAR BIOLOGY-CHEMISTRY, MEDICINAL
CiteScore
9.20
自引率
4.00%
发文量
323
审稿时长
1 months
期刊介绍: ACS Chemical Neuroscience publishes high-quality research articles and reviews that showcase chemical, quantitative biological, biophysical and bioengineering approaches to the understanding of the nervous system and to the development of new treatments for neurological disorders. Research in the journal focuses on aspects of chemical neurobiology and bio-neurochemistry such as the following: Neurotransmitters and receptors Neuropharmaceuticals and therapeutics Neural development—Plasticity, and degeneration Chemical, physical, and computational methods in neuroscience Neuronal diseases—basis, detection, and treatment Mechanism of aging, learning, memory and behavior Pain and sensory processing Neurotoxins Neuroscience-inspired bioengineering Development of methods in chemical neurobiology Neuroimaging agents and technologies Animal models for central nervous system diseases Behavioral research
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