Vendrell Marc, Angulo Ester, Casadó Vicent, Lluis Carme, Franco Rafael, Albericio Fernando, Royo Miriam
Combinatorial Chemistry Unit, Barcelona Science Park, Department of Biochemistry and Molecular Biology, Molecular Neurobiology Unit, IDIBAPS, Institut d'Investigacions Biomèdiques August Pi i Sunyer, IRB Barcelona, Barcelona Science Park, Barcelona, Spain.
J Med Chem. 2007 Jun 28;50(13):3062-9. doi: 10.1021/jm060947x. Epub 2007 Jun 1.
Multivalent ligands are promising pharmacological tools that may be more efficacious for several diseases than highly selective single-target drugs. A combined therapy using dopaminergic agonists and adenosinergic antagonists is currently being evaluated for the treatment of Parkinson's disease. [(a) Kanda, T.; et al. Exp. Neurol. 2000, 162, 321-327. (b) Jenner, P. Expert Opin. Invest. Drugs 2005, 14, 729-738. (c) Kase, H.; et al. Neurology 2003, 61 (Suppl 6), S97-S100.] Here we prepared dual ligands acting on adenosine and dopamine receptors by applying a combinatorial approach based on the ergolene privileged structure. The potency and efficacy of these novel compounds were determined by radioligand binding studies and intracellular cAMP production assays in cells expressing adenosine and dopamine receptors. Selected compounds displayed dual dopamine agonist and adenosine antagonist activity. Molecules with this pharmacological profile are potentially useful for studying dopamine-adenosine cross-talk in the central nervous system and for testing the therapeutic potential of multivalent drugs for Parkinson's disease.
多价配体是很有前景的药理学工具，对于几种疾病而言，它们可能比高选择性的单靶点药物更有效。目前正在评估一种使用多巴胺能激动剂和腺苷能拮抗剂的联合疗法用于治疗帕金森病。[（a）神田，T.；等人。《实验神经病学》2000年，162卷，321 - 327页。（b）詹纳，P.《药物研发专家意见》2005年，14卷，729 - 738页。（c）加世，H.；等人。《神经病学》2003年，61卷（增刊6），S97 - S100页。]在此，我们通过应用基于麦角灵特权结构的组合方法制备了作用于腺苷和多巴胺受体的双配体。这些新型化合物的效力和效能通过放射性配体结合研究以及在表达腺苷和多巴胺受体的细胞中的细胞内cAMP生成测定来确定。所选化合物表现出多巴胺激动剂和腺苷拮抗剂的双重活性。具有这种药理学特征的分子对于研究中枢神经系统中的多巴胺 - 腺苷相互作用以及测试多价药物治疗帕金森病的潜力可能是有用的。
