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首页> 外文期刊>Journal of Medicinal Chemistry >Synthesis and pharmacological profiling of analogues of benzyl quinolone carboxylic acid (BQCA) as allosteric modulators of the M_1 muscarinic receptor
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Synthesis and pharmacological profiling of analogues of benzyl quinolone carboxylic acid (BQCA) as allosteric modulators of the M_1 muscarinic receptor

机译：M_1毒蕈碱受体变构调节剂苄基喹诺酮羧酸（BQCA）类似物的合成和药理作用

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摘要

Established therapy in Alzheimer's disease involves potentiation of the endogenous orthosteric ligand, acetylcholine, at the M1 muscarinic receptors found in higher concentrations in the cortex and hippocampus. Adverse effects, due to indiscriminate activation of other muscarinic receptor subtypes, are common. M_1 muscarinic positive allosteric modulators/allosteric agonists such as BQCA offer an attractive solution, being exquisitely M _1-selective over other muscarinic subtypes. A common difficulty with allosteric ligands is interpreting SAR, based on composite potency values derived in the presence of fixed concentration of agonist. In reality these values encompass multiple pharmacological parameters, each potentially and differentially sensitive to structural modification of the ligand. We report novel BQCA analogues which appear to augment ligand affinity for the receptor (pK_B), intrinsic efficacy (τ_B), and both binding (α) and functional (β) cooperativity with acetylcholine. Ultimately, development of such enriched SAR surrounding allosteric modulators will provide insight into their mode of action.
机译：在阿尔茨海默氏病中建立的治疗方法涉及在皮质和海马中较高浓度的M1毒蕈碱受体上增强内源性正构配体乙酰胆碱。由于其他毒蕈碱受体亚型的不加选择的激活，不良反应是常见的。 M_1毒蕈碱阳性变构调节剂/变构激动剂（例如BQCA）提供了一种有吸引力的解决方案，与其他毒蕈碱亚型相比，M _1选择性出色。基于在固定浓度的激动剂存在下得出的复合效能值，变构配体的常见困难是解释SAR。实际上，这些值包括多个药理学参数，每个参数对配体的结构修饰潜在且不同。我们报告了新型的BQCA类似物，似乎增加了配体对受体的亲和力（pK_B），内在功效（τ_B），以及与乙酰胆碱的结合（α）和功能（β）协同作用。最终，围绕变构调节剂的这种富集SAR的开发将提供对其作用方式的洞察力。

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