Soares-da-Silva Patrício, Vieira-Coelho Maria A, Parada António
Department of Research & Development, BIAL, S. Mamede do Coronado, Portugal.
Pharmacol Toxicol. 2003 Jun;92(6):272-8. doi: 10.1034/j.1600-0773.2003.920604.x.
The present study evaluated the relationship between the degree of catechol-O-methyltransferase (COMT) inhibition in erythrocytes and liver by BIA 3-202 (1-[3,4-dihydroxy-5-nitrophenyl]-2-phenyl-ethanone) and determined its effects upon the O-methylation of L-DOPA in rats orally treated with L-DOPA plus benserazide. The soluble form of COMT (S-COMT) in erythrocytes was endowed with the same affinity as liver S-COMT for the substrate adrenaline. BIA 3-202 inhibited erythrocytes and liver S-COMT with ED50's of 1.9 (0.7, 3.1) and 1.9 (0.5, 3.2) (95% confidence limits) mg kg(-1), respectively. BIA 3-202 reduced the L-DOPA-induced rise of 3-O-methyl-L-DOPA in the peripheral circulation, striatal dialysate levels and striatum, and increased dopamine striatal levels. In BIA 3-202-treated rats the increase in L-DOPA in peripheral blood and striatal dialysates was significantly greater than in vehicle-treated rats. It is concluded that S-COMT activity in erythrocytes may provide important information on the pharmacodynamic profile of COMT inhibitors. The novel COMT inhibitor BIA 3-202 is a potent COMT inhibitor that enhances the availability of L-DOPA to the brain by reducing its O-methylation, which may prove beneficial in patients with Parkinson's disease treated with L-DOPA.
本研究评估了BIA 3-202（1-[3,4-二羟基-5-硝基苯基]-2-苯基乙酮）对红细胞和肝脏中儿茶酚-O-甲基转移酶（COMT）的抑制程度，并确定了其对口服左旋多巴加苄丝肼的大鼠体内左旋多巴O-甲基化的影响。红细胞中的可溶性COMT（S-COMT）对底物肾上腺素的亲和力与肝脏S-COMT相同。BIA 3-202抑制红细胞和肝脏S-COMT的半数有效剂量（ED50）分别为1.9（0.7，3.1）和1.9（0.5，3.2）（95%置信限）mg kg(-1)。BIA 3-202降低了外周循环、纹状体透析液水平和纹状体中左旋多巴诱导的3-O-甲基-L-多巴的升高，并增加了纹状体多巴胺水平。在BIA 3-202处理的大鼠中，外周血和纹状体透析液中左旋多巴的增加显著大于溶剂处理的大鼠。结论是，红细胞中的S-COMT活性可能为COMT抑制剂的药效学特征提供重要信息。新型COMT抑制剂BIA 3-202是一种有效的COMT抑制剂，通过减少左旋多巴的O-甲基化来提高其向脑内的可用性，这可能对用左旋多巴治疗的帕金森病患者有益。
