肌肉蛋白受体M1的Allosteric调节剂增强了乙胆的有效性,并降低了斑马鱼的运动活动和转向行为
Corey J Widman1, Sestina Ventresca2, Jillian Dietrich2
1Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Mail Stop #1015, 3000 Arlington Ave., Toledo, OH, 43614, USA.
Scientific reports
|June 28, 2024
概括
针对肌肉酸乙胆受体 (mAChR) 的新型阳性全调节剂 (PAM) 增强了G蛋白的疗效,显示出治疗自闭症谱系障碍 (ASD) 中的神经系统疾病和重复性行为的前景.
科学领域:
- 神经科学是一个神经科学.
- 药理学 药理学是指药理学的学科.
背景情况:
- 肌肉酸乙胆受体 (mAChR) 的全调节是神经疾病治疗的关键策略.
- 大多数积极的全调节剂 (PAM) 增强激素的亲和力,但很少有增强G蛋白合效率.
研究的目的:
- 为了确定增强mAChR疗效的amiodarone的结构特征.
- 开发具有提高疗效,安全性和结合亲和力的新型mAChR PAM.
主要方法:
- 研究了表达M1受体的CHO细胞中阿米奥达龙的结构特征.
- 将这些特征纳入n-基异氨酸中,以创建混合联结体.
- 在斑马鱼中选化合物以检测体内毒性和行为影响.
主要成果:
- 新型配体显示了增强的mAChR疗效,较低的毒性和比阿米奥达龙更高的结合亲和力.
- 化合物8a和8c分别表现出最强的结合亲和力和有效性.
- 斑马鱼的研究表明,选择性化合物减少了运动运动活动,增加了转行为.
结论:
- 对mAChR疗效的Allosteric调节为神经精神疾病,包括自闭症谱系障碍 (ASD) 提供了潜在的治疗方法.
- 结合阿米奥达龙的疗效增强特征与n-伊沙的混合体,代表了一个有前途的mAChR调节器类.
相关概念视频
Cholinergic Receptors: Muscarinic
2.1K
The pharmacological actions of acetylcholine are elicited via its binding to two families of cholinergic receptors or cholinoceptors, namely, muscarinic and nicotinic receptors. Muscarinic receptors are G protein-coupled receptors and have five subtypes, M1–M5. All mAChR subtypes are activated by acetylcholine and blocked by the antagonist, atropine.
The subtypes M1, M3, and M5 couple with the Gq subunit and activate the phospholipase C (PLC) activity, mobilizing intracellular Ca2+....
The subtypes M1, M3, and M5 couple with the Gq subunit and activate the phospholipase C (PLC) activity, mobilizing intracellular Ca2+....
2.1K
Direct-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship
935
Cholinergic agonists or cholinomimetics mimic the action of acetylcholine to stimulate the parasympathetic nervous system. They are categorized into direct-acting and indirect-acting agents. The direct-acting cholinergic drugs induce the parasympathetic response by directly binding to the muscarinic or nicotine receptors. In comparison, the indirect-acting cholinergic drugs prevent acetylcholine hydrolysis, indirectly contributing to the extended parasympathetic response.
The direct-acting...
The direct-acting...
935
Direct-Acting Cholinergic Agonists: Pharmacological Actions
1.3K
Direct-acting cholinergic agonists exert their pharmacological actions by mimicking the effects of acetylcholine on postsynaptic muscarinic receptors to generate parasympathetic responses. These agents elicit a range of physiological responses, including cardiovascular effects. For example, activation of muscarinic receptors induces bradycardia, decreased cardiac output, reduced peripheral resistance, and consequent hypotension. In the eye, stimulation of M3 receptors leads to smooth muscle...
1.3K
Indirect-Acting Cholinergic Agonists: Pharmacological Actions
658
Indirect-acting cholinergic agonists, also known as anticholinesterases, exert their pharmacological effects by enhancing cholinergic transmission in various body parts, including the neuromuscular junction, autonomic cholinergic synapses, and the brain.
At the neuromuscular junction, these agents work by inhibiting the breakdown of acetylcholine, allowing it to remain bound to the receptor and bind to nearby receptors. This process leads to repetitive firing of the endplate, causing muscle...
At the neuromuscular junction, these agents work by inhibiting the breakdown of acetylcholine, allowing it to remain bound to the receptor and bind to nearby receptors. This process leads to repetitive firing of the endplate, causing muscle...
658
Direct-Acting Cholinergic Agonists: Pharmacokinetics
1.1K
Direct-acting cholinergic agonists, such as synthetic choline esters and naturally occurring alkaloids, exert their effects by enhancing the actions of acetylcholine and stimulating the parasympathetic nervous system. Synthetic choline esters share structural similarities with acetylcholine. For example, they have a positively charged quaternary ammonium or onium group, contributing to their hydrophilic characteristics. As a result, they are poorly absorbed in the body through oral...
1.1K
Cholinergic Antagonists: Pharmacological Actions
1.1K
Antimuscarinic drugs block muscarinic receptors in multiple systems, including the gut, eye, smooth muscles, respiratory tract, cardiovascular, and central nervous systems. They produce similar effects with varying selectivity depending on the specific agent and tissue. Here are the key pharmacological actions of antimuscarinics:
Gastrointestinal Effects: Antimuscarinics reduce gut contractions, increase gastric emptying, and slow intestinal transit. They partly inhibit gastric acid secretion...
Gastrointestinal Effects: Antimuscarinics reduce gut contractions, increase gastric emptying, and slow intestinal transit. They partly inhibit gastric acid secretion...
1.1K


