Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.
Trends Pharmacol Sci. 2010 Dec;31(12):575-9. doi: 10.1016/j.tips.2010.09.002. Epub 2010 Oct 18.
Unlike nanocarriers that are intended to release their drug cargo at the site of action, biocompatibile polyamidoamine (PAMAM) conjugates are designed to act at cell surface G protein-coupled receptors (GPCRs) without drug release. These multivalent GPCR ligand-dendrimer (GLiDe) conjugates display qualitatively different pharmacological properties in comparison with monomeric drugs. They might be useful as novel tools to study GPCR homodimers and heterodimers as well as higher aggregates. The structure of the conjugate determines the profile of biological activity, receptor selectivity, and physical properties such as water solubility. Prosthetic groups for characterization and imaging of receptors can be introduced without loss of affinity. The feasibility of targeting multiple adenosine and P2Y receptors for synergistic effects has been shown. Testing in vivo will be needed to explore the effects on pharmacokinetics and tissue targeting.
与旨在在作用部位释放药物货物的纳米载体不同,生物相容的聚酰胺-胺(PAMAM)缀合物旨在在细胞表面 G 蛋白偶联受体(GPCR)上发挥作用而不释放药物。与单体药物相比,这些多价 GPCR 配体-树枝状大分子(GLiDe)缀合物表现出定性不同的药理学特性。它们可能是研究 GPCR 同二聚体和异二聚体以及更高聚集体的有用新工具。缀合物的结构决定了生物活性、受体选择性以及物理性质(如水溶性)的特征。可以在不损失亲和力的情况下引入用于受体的表征和成像的附加基团。已经证明了靶向多种腺苷和 P2Y 受体以产生协同作用的可行性。需要进行体内测试以探索对药代动力学和组织靶向的影响。