更新于：2024-11-21

BRL-54443

更新于：2024-11-21

概要

研发状态

概要

基本信息

药物类型

小分子化药

别名

靶点

5-HT receptor x 5-HT1F receptor

作用机制

5-HT receptor激动剂(5-羟色胺受体激动剂)、5-HT1F receptor激动剂(5-羟色胺1F受体激动剂)

治疗领域-

在研适应症-

非在研适应症-

原研机构

Smithkline Beecham Pharmaceuticals (India) Ltd.

在研机构-

非在研机构

Smithkline Beecham Pharmaceuticals (India) Ltd.

最高研发阶段无进展药物发现

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构

分子式C14H18N2O

InChIKeyWKNFADCGOAHBPG-UHFFFAOYSA-N

CAS号57477-39-1

关联

100 项与 BRL-54443 相关的临床结果

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100 项与 BRL-54443 相关的转化医学

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100 项与 BRL-54443 相关的专利（医药）

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项与 BRL-54443 相关的文献（医药）

2022-12-01·Biochimie3区 · 生物学

Serotonergic drugs modulate the phase behavior of complex lipid bilayers

3区 · 生物学

Article

作者: Huster, Daniel ; Roy, Debsankar Saha ; Musabirova, Guzel ; Gupta, Ankur ; Maiti, Sudipta ; Engberg, Oskar

Serotonin is an endogenous neurotransmitter involved in both physiological and pathophysiological processes. Traditionally, serotonin acts as a ligand for G protein-coupled receptors (GPCRs) leading to subsequent cell signaling. However, serotonin can also bind to lipid membranes with high affinity and modulate the phase behavior in 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC)/N-palmitoyl-D-erythro-sphingosylphosphorylcholine (PSM)/cholesterol model membranes mimicking the outer leaflet of the plasma membrane. Here, we investigated if serotonergic drugs containing the pharmacophore from serotonin would also modulate phase behavior in lipid membranes in a similar fashion. We used ²H NMR spectroscopy to explore the phase behavior of POPC/PSM/cholesterol (4/4/2 molar ratio) mixtures in the presence of the serotonergic drugs aripiprazole, BRL-54443, BW-723C86, and CP-135807 at a lipid to drug molar ratio of 10:1. POPC and PSM were perdeuterated in the palmitoyl chain, respectively, and prepared in individual samples. Numerical lineshape simulations of the ²H NMR spectra were used to calculate the order parameter profiles and projected lengths of the saturated acyl chains. All serotonergic drugs induce two components in ²H NMR spectra, indicating that they increased the hydrophobic mismatch between the thickness of the coexisting lipid phases leading to larger domain sizes, relatively similarly to serotonin. AFM force indentation and Raman spectral studies, which interrogate membrane mechanical properties, also indicate changes in membrane order in the presence of these drugs. These findings highlight how serotonergic drugs alter membrane phase behavior and could modulate both target and other membrane proteins, possibly explaining the side effects observed for serotonergic and other clinically relevant drugs.

2021-04-15·Nature1区 · 综合性期刊

Structural insights into the lipid and ligand regulation of serotonin receptors

1区 · 综合性期刊

Article

作者: Melcher, Karsten ; Guo, Jia ; Jiang, Yi ; Shen, Dan-Dan ; Zhang, Huibing ; Jiang, Hualiang ; Mao, Chunyou ; Robinson, Carol V ; Simon, Icaro A ; Svensson, Bo ; Huang, Sijie ; Cheng, Xi ; Harpsøe, Kasper ; Zhou, X Edward ; Xu, Peiyu ; Yen, Hsin-Yung ; Zhang, Yan ; Gloriam, David E ; Xu, H Eric

Serotonin, or 5-hydroxytryptamine (5-HT), is an important neurotransmitter^1,2 that activates the largest subtype family of G-protein-coupled receptors³. Drugs that target 5-HT_1A, 5-HT_1D, 5-HT_1E and other 5-HT receptors are used to treat numerous disorders⁴. 5-HT receptors have high levels of basal activity and are subject to regulation by lipids, but the structural basis for the lipid regulation and basal activation of these receptors and the pan-agonism of 5-HT remains unclear. Here we report five structures of 5-HT receptor-G-protein complexes: 5-HT_1A in the apo state, bound to 5-HT or bound to the antipsychotic drug aripiprazole; 5-HT_1D bound to 5-HT; and 5-HT_1E in complex with a 5-HT_1E- and 5-HT_1F-selective agonist, BRL-54443. Notably, the phospholipid phosphatidylinositol 4-phosphate is present at the G-protein-5-HT_1A interface, and is able to increase 5-HT_1A-mediated G-protein activity. The receptor transmembrane domain is surrounded by cholesterol molecules-particularly in the case of 5-HT_1A, in which cholesterol molecules are directly involved in shaping the ligand-binding pocket that determines the specificity for aripiprazol. Within the ligand-binding pocket of apo-5-HT_1A are structured water molecules that mimic 5-HT to activate the receptor. Together, our results address a long-standing question of how lipids and water molecules regulate G-protein-coupled receptors, reveal how 5-HT acts as a pan-agonist, and identify the determinants of drug recognition in 5-HT receptors.

2017-12-01·Clinical and Experimental Pharmacology and Physiology4区 · 医学

5‐HT modulates the rat mesenteric vasopressor outflow by 5‐HT_1D sympatholytic receptors

4区 · 医学

Article

作者: Rodríguez‐Barbero, Alicia ; García‐Domingo, Mónica ; Morán, Asunción ; Gómez‐Roso, Miriam ; Martín, María‐Luisa ; García‐Pedraza, José‐Ángel

Summary5‐hydroxytryptamine (5‐HT) modulates noradrenergic activity in different cardiovascular territories, but its effect on the mesenteric vasopressor outflow has not yet been clarified. This study investigated the in vivo serotonergic influence, characterizing 5‐HT receptors implicated, in sympathetic innervation of mesenteric vasculature. Wistar rats were anaesthetised and prepared for the in situ autoperfused rat mesentery, monitoring systemic blood pressure (SBP), heart rate (HR) and mesenteric perfusion pressure (MPP). Electrical stimulation of mesenteric sympathetic nerves resulted in frequency‐dependent increases in MPP (9 ± 1.6, 25.7 ± 3.9 and 60.2 ± 5 mmHg for 2, 4 and 8 Hz, respectively), without altering SBP or HR. 5‐HT (1‐25 μg/kg), 5‐carboxamidotryptamine (5‐HT1/7 agonist; 25 μg/kg) or L‐694,247 (5‐HT1D agonist; 1‐25 μg/kg) i.a. bolus inhibited vasopressor responses by mesenteric nerves electrical stimulation, unlike i.a. bolus of agonists 8‐OH‐DPAT (5‐HT1A), CGS‐12066B (5‐HT1B), BRL 54443 (5‐HT1e/1F), α‐methyl‐5‐HT (5‐HT2), 1‐PBG (5‐HT3), cisapride (5‐HT4) or AS‐19 (5‐HT7) (25 μg/kg each). Interestingly, i.a. L‐694,247 (25 μg/kg) also reduced the exogenous norepinephrine‐induced vasoconstrictions. Pretreatment with selective 5‐HT1D receptor antagonist, LY310762 (1 mg/kg, i.v.), completely abolished L‐694,247‐ and 5‐HT‐induced mesenteric sympathoinhibition. Furthermore, ELISA analysis confirmed 5‐HT1D receptors expression in mesenteric artery. These findings suggest that serotonergic mechanisms‐induced sympathoinhibition of mesenteric noradrenergic outflow is mediated by pre and/or postjunctional 5‐HT1D receptors.

100 项与 BRL-54443 相关的药物交易

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