Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD. United States.
Curr Neuropharmacol. 2018 Jan 30;16(2):222-230. doi: 10.2174/1570159X15666170518151127.
Dopamine D2 and D3 receptors can form homo- and heterodimers and are important targets in Schizophrenia and Parkinson's. Recently, many efforts have been made to pharmacologically target these receptor complexes. This review focuses on various strategies to act specifically on dopamine receptor dimers, that are transiently formed.
Various binding and functional assays were reviewed to study the properties of bivalent ligands, particularly for the dualsteric compound SB269,652. The dimerization of D2 and D3 receptors were analyzed by using single particle tracking microscopy.
The specific targeting of dopamine D2 and D3 dimers can be achieved with bifunctional ligands, composed of two pharmacophores binding the two orthosteric sites of the dimeric complex. If the target is a homodimer, then the ligand is homobivalent. Instead, if the target is a heterodimer, then the ligand is heterobivalent. However, there is some concern regarding pharmacokinetics and binding properties of such drugs. Recently, a new generation of bitopic compounds with dualsteric properties have been discovered that bind to the orthosteric and the allosteric sites in one monomeric receptor. Regarding dopamine D2 and D3 receptors, a new dualsteric molecule SB269,652 was shown to have selective negative allosteric properties across D2 and D3 homodimers, but it behaves as an orthosteric antagonist on receptor monomer. Targeting dimers is also complicated as they are transiently formed with varying monomer/dimer ratio. Furthermore, this ratio can be altered by administering an agonist or a bifunctional antagonist.
Last 15 years have witnessed an explosive amount of work aimed at generating bifunctional compounds as a novel strategy to target GPCR homo- and heterodimers, including dopamine receptors. Their clinical use is far from trivial, but, at least, they have been used to validate the existence of receptor dimers in-vitro and in-vivo. The dualsteric compound SB269, 652, with its peculiar pharmacological profile, may offer therapeutic advantages and a better tolerability in comparison with pure antagonists at D2 and D3 receptors and pave the way for a new generation of antipsychotic drugs.
多巴胺 D2 和 D3 受体可以形成同型和异型二聚体，是精神分裂症和帕金森病的重要靶点。最近，人们已经做出了许多努力来对这些受体复合物进行药理学靶向治疗。本综述重点关注了各种特异性作用于多巴胺受体二聚体的策略，这些二聚体是瞬时形成的。
综述了各种结合和功能测定方法，以研究双价配体的特性，特别是双功能化合物 SB269,652。使用单颗粒跟踪显微镜分析 D2 和 D3 受体的二聚化。
通过由两个结合二聚体复合物两个正位点的药效团组成的双功能配体，可以实现对多巴胺 D2 和 D3 二聚体的特异性靶向。如果靶标是同型二聚体，则配体是同价的。相反，如果靶标是异型二聚体，则配体是异价的。然而，人们对这些药物的药代动力学和结合特性存在一些担忧。最近，发现了具有双位性质的新一代双位化合物，它们可以结合一个单体受体的正位和变构位。关于多巴胺 D2 和 D3 受体，新的双功能分子 SB269,652 被证明对 D2 和 D3 同型二聚体具有选择性的负变构性质，但在受体单体上表现为正位拮抗剂。由于二聚体是瞬时形成的，并且单体/二聚体比例不同，因此靶向二聚体也很复杂。此外，通过给予激动剂或双功能拮抗剂可以改变这种比例。
过去 15 年见证了大量旨在生成双功能化合物的工作，这是一种针对 GPCR 同型和异型二聚体的新策略，包括多巴胺受体。它们的临床应用远非微不足道，但至少它们已被用于在体外和体内验证受体二聚体的存在。双功能化合物 SB269,652 具有特殊的药理学特性，与 D2 和 D3 受体的纯拮抗剂相比，可能具有治疗优势和更好的耐受性，并为新一代抗精神病药物铺平道路。
