Vlok Nevil, Malan Sarel F, Castagnoli Neal, Bergh Jacobus J, Petzer Jacobus P
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
Bioorg Med Chem. 2006 May 15;14(10):3512-21. doi: 10.1016/j.bmc.2006.01.011. Epub 2006 Jan 26.
The adenosine A2A receptor has emerged as a possible target for the treatment of Parkinson's disease (PD). Evidence suggests that antagonism of the A2A receptor not only improves the symptoms of the disease but may also protect against the underlying degenerative processes. We have recently reported that several known adenosine A2A receptor antagonists (A2A antagonists) also are moderate to very potent inhibitors of monoamine oxidase B (MAO-B). The most potent among these was (E)-8-(3-chlorostyryl)caffeine (CSC), a compound frequently used when examining the in vivo pharmacological effects of A2A antagonists. Since MAO-B inhibitors are also thought to possess antiparkinsonian properties, dual targeting drugs that block both MAO-B and A2A receptors may have enhanced therapeutic potential in the treatment of PD. In this study, we prepared selected analogues of CSC in an attempt to examine specific structural features that may be important for potent MAO-B inhibition. The results of a SAR study established that the potency of MAO-B inhibition by (E)-8-styrylcaffeinyl analogues depends upon the van der Waals volume (V(w)), lipophilicity (pi), and the Hammett constant (sigma(m)) of the substituents attached to C-3 of the phenyl ring of the styryl moiety. Potency also varies with substituents attached to C-4 with bulkiness (V(w)) and lipophilicity (pi) being the principal substituent descriptors.
腺苷A2A受体已成为治疗帕金森病（PD）的一个可能靶点。有证据表明，A2A受体拮抗作用不仅能改善疾病症状，还可能预防潜在的退行性病变过程。我们最近报道，几种已知的腺苷A2A受体拮抗剂（A2A拮抗剂）也是单胺氧化酶B（MAO - B）的中度至强效抑制剂。其中最有效的是（E）-8-（3-氯苯乙烯基）咖啡因（CSC），这是一种在研究A2A拮抗剂的体内药理作用时常用的化合物。由于MAO - B抑制剂也被认为具有抗帕金森病特性，同时阻断MAO - B和A2A受体的双重靶向药物在治疗PD方面可能具有更高的治疗潜力。在本研究中，我们制备了CSC的特定类似物，试图研究对强效抑制MAO - B可能重要的特定结构特征。一项构效关系（SAR）研究结果表明，（E）-8-苯乙烯基咖啡因类似物对MAO - B的抑制效力取决于苯乙烯基部分苯环C-3位上取代基的范德华体积（V(w)）、亲脂性（π）和哈米特常数（σ(m)）。效力也会因C-4位上的取代基而变化，取代基的体积（V(w)）和亲脂性（π）是主要的取代基描述符。
