PDF(Pubmed)
Abstract：
Translation of muscarinic acetylcholine receptor (mAChR) agonists into clinically used therapeutic agents has been difficult due to their poor subtype selectivity. M4 mAChR subtype-selective positive allosteric modulators (PAMs) may provide better therapeutic outcomes, hence investigating their detailed pharmacological properties is crucial to advancing them into the clinic. Herein, we report the synthesis and comprehensive pharmacological evaluation of M4 mAChR PAMs structurally related to 1e, Me-C-c, [11C]MK-6884 and [18F]12. Our results show that small structural changes to the PAMs can result in pronounced differences to baseline, potency (pEC50) and maximum effect (Emax) measures in cAMP assays when compared to the endogenous ligand acetylcholine (ACh) without the addition of the PAMs. Eight selected PAMs were further assessed to determine their binding affinity and potential signalling bias profile between cAMP and β-arrestin 2 recruitment. These rigorous analyses resulted in the discovery of the novel PAMs, 6k and 6l, which exhibit improved allosteric properties compared to the lead compound, and probative in vivo exposure studies in mice confirmed that they maintain the ability to cross the blood-brain barrier, making them more suitable for future preclinical assessment.
摘要：
毒蕈碱乙酰胆碱受体(mAChR)激动剂转化为临床使用的治疗剂是困难的,因为它们的亚型选择性差。M4mAChR亚型选择性正变构调节剂（PAMs）可以提供更好的治疗结果，因此，研究它们详细的药理特性对于推进它们进入临床至关重要。在这里，我们报道了与1e结构相关的M4mAChRPAMs的合成和综合药理评价，Me-C-C,[11C]MK-6884和[18F]12。我们的结果表明，PAMs的微小结构变化可以导致与基线的明显差异，与不添加PAM的内源性配体乙酰胆碱（ACh）相比，cAMP测定中的效力（pEC50）和最大效应（Emax）测量进一步评估了八个选定的PAM，以确定其结合亲和力和cAMP和β-抑制蛋白2募集之间的潜在信号传导偏倚谱。这些严格的分析导致了新型PAM的发现，6k和6l，与铅化合物相比，它表现出改进的变构特性，并且在小鼠体内进行的证明性体内暴露研究证实，它们保持穿过血脑屏障的能力，使其更适合未来的临床前评估。
