Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, University of Leiden, Einsteinweg 55, 2333 AR, The Netherlands; Department of Molecular Physiology, Leiden Institute of Chemistry, University of Leiden, Einsteinweg 55, 2333 AR, The Netherlands.
Department of Molecular Physiology, Leiden Institute of Chemistry, University of Leiden, Einsteinweg 55, 2333 AR, The Netherlands.
Biochem Pharmacol. 2018 Jun;152:129-142. doi: 10.1016/j.bcp.2018.03.018. Epub 2018 Mar 21.
A decade ago, the drug-target residence time model has been (re-)introduced, which describes the importance of binding kinetics of ligands on their protein targets. Since then, it has been applied successfully for multiple protein targets, including GPCRs, for the development of lead compounds with slow dissociation kinetics (i.e. long target residence time) to increase in vivo efficacy or with short residence time to prevent on-target associated side effects. To date, this model has not been applied in the design and pharmacological evaluation of novel selective ligands for the cannabinoid CB receptor (CBR), a GPCR with therapeutic potential in the treatment of tissue injury and inflammatory diseases. Here, we have investigated the relationships between physicochemical properties, binding kinetics and functional activity in two different signal transduction pathways, G protein activation and β-arrestin recruitment. We synthesized 24 analogues of 3-cyclopropyl-1-(4-(6-((1,1-dioxidothiomorpholino)methyl)-5-fluoropyridin-2-yl)benzyl)imidazoleidine-2,4-dione (LEI101), our previously reported in vivo active and CBR-selective agonist, with varying basicity and lipophilicity. We identified a positive correlation between target residence time and functional potency due to an increase in lipophilicity on the alkyl substituents, which was not the case for the amine substituents. Basicity of the agonists did not show a relationship with affinity, residence time or functional activity. Our findings provide important insights about the effects of physicochemical properties of the specific substituents of this scaffold on the binding kinetics of agonists and their CBR pharmacology. This work therefore shows how CBR agonists can be designed to have optimal kinetic profiles, which could aid the lead optimization process in drug discovery for the study or treatment of inflammatory diseases.
十年前，药物-靶标停留时间模型（drug-target residence time model）被重新引入，该模型描述了配体与蛋白质靶标结合的动力学对其重要性。从那时起，它已成功应用于多个蛋白质靶标，包括 G 蛋白偶联受体（GPCR），用于开发具有缓慢解离动力学（即长靶标停留时间）的先导化合物，以提高体内疗效，或具有短停留时间以防止与靶标相关的副作用。迄今为止，该模型尚未应用于新型选择性大麻素 CB 受体（CBR）配体的设计和药理学评估，CBR 是一种在治疗组织损伤和炎症性疾病方面具有治疗潜力的 GPCR。在这里，我们研究了两种不同信号转导途径（G 蛋白激活和β-arrestin 募集）中理化性质、结合动力学和功能活性之间的关系。我们合成了 24 种 3-环丙基-1-（4-（6-（（1,1-二氧代硫代吗啉基）甲基）-5-氟吡啶-2-基）苄基）咪唑烷-2,4-二酮（LEI101）的类似物，LEI101 是我们之前报道的具有体内活性和 CBR 选择性的激动剂，具有不同的碱性和亲脂性。我们发现，由于烷基取代基的亲脂性增加，导致靶标停留时间与功能效力之间呈正相关，而对于胺取代基则不然。激动剂的碱性与亲和力、停留时间或功能活性之间没有关系。我们的研究结果提供了有关该支架特定取代基的理化性质对激动剂结合动力学及其 CBR 药理学的影响的重要见解。因此，这项工作表明如何设计 CBR 激动剂以具有最佳的动力学特征，这可能有助于炎症性疾病的研究或治疗药物发现过程中的先导化合物优化。
