Parada António, Soares-da-Silva Patrício
Department of Research and Development, BIAL, S. Mamede do Coronado, Portugal.
Pharmacology. 2003 May;68(1):29-37. doi: 10.1159/000068730.
The present study aims at determining the effects of the catechol-O-methyltransferase (COMT) inhibitor BIA 3-202 [1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone] upon levels of L-3,4-dihydroxyphenylalanine (L-DOPA) and metabolites in peripheral circulation (jugular vein), whole brain, and striatal microdialysates in rats orally treated with L-DOPA plus benserazide. A low dose (3 mg/kg) of BIA 3-202 was relatively selective to inhibit liver COMT, being devoid of major significant inhibitory effects upon brain COMT. By contrast, a high dose (30 mg/kg) of BIA 3-202 markedly inhibited liver and brain COMT. BIA 3-202 (3 and 30 mg/kg) reduced the L-DOPA-induced rise of 3-O-methyl-L-DOPA in the peripheral circulation (jugular vein), brain tissue, and striatal dialysate, but failed to increase the levels of dopamine in striatal dialysates despite the increase in dopamine brain levels. However, the changes in brain levels of L-DOPA, 3-O-methyl-L-DOPA, and dopamine and in striatal dialysate levels of L-DOPA and 3-O-methyl-L-DOPA, obtained with 3 mg/kg BIA 3-202, were not different from those obtained with 30 mg/kg BIA 3-202. In conclusion, inhibition of peripheral COMT by BIA 3-202 may suffice to improve the availability of L-DOPA to the brain.
本研究旨在确定儿茶酚-O-甲基转移酶（COMT）抑制剂BIA 3-202[1-(3,4-二羟基-5-硝基苯基)-2-苯基乙酮]对口服左旋多巴加苄丝肼的大鼠外周循环（颈静脉）、全脑和纹状体微透析液中L-3,4-二羟基苯丙氨酸（L-DOPA）及其代谢产物水平的影响。低剂量（3 mg/kg）的BIA 3-202对抑制肝脏COMT具有相对选择性，对脑COMT无明显主要抑制作用。相比之下，高剂量（30 mg/kg）的BIA 3-202可显著抑制肝脏和脑COMT。BIA 3-202（3和30 mg/kg）可降低外周循环（颈静脉）、脑组织和纹状体透析液中L-DOPA诱导的3-O-甲基-L-DOPA升高，但尽管纹状体多巴胺脑水平升高，却未能增加纹状体透析液中多巴胺的水平。然而，3 mg/kg BIA 3-202导致的脑L-DOPA、3-O-甲基-L-DOPA和多巴胺水平变化以及纹状体透析液中L-DOPA和3-O-甲基-L-DOPA水平变化与30 mg/kg BIA 3-202导致的变化并无差异。总之，BIA 3-202对外周COMT的抑制可能足以提高L-DOPA向脑内的可用性。
