Mele L, Massotti M, Gatta F
Laboratorio di Farmacologia, Istituto Superiore di Sanità, Roma, Italy.
Pharmacol Biochem Behav. 1988 May;30(1):5-11. doi: 10.1016/0091-3057(88)90418-2.
The effects of 3-methoxycarbonyl- (beta-CCM, Ia), 3-ethoxycarbonyl- (beta-CCE, Ic), 3-propoxycarbonyl- (PrCC, Ie), 3-N-methylcarboxamido- (FG-7142, Ig) beta-carboline and 2-acetyl-3-methoxycarbonyl-1,2-dihydro-beta-carboline (IIa) as well as of their corresponding 9-acetyl derivatives (Ib, Id, If, Ih and IIb) have been studied in rabbits. In addition, the effects of 6,7-dimethoxy-4-ethyl-3-methoxycarbonyl-beta-carboline (DMCM) have also been studied. In in vitro studies, these drugs compete with 3H-diazepam to benzodiazepine (BDZ) receptor in membrane preparations from brain cortex. The values of IC50 are in the nanomolar range without significant differences between the acetyl derivatives and their congeners only compound If shows a 10-fold decrease of the binding capacity in respect to its congener Ie. In the presence of 10(-5) M GABA, a decrease in the binding capacity for DMCM, Ia, Ic and Ig and an increase for If are observed. In vivo studies show that DMCM, Ia, Ib, IIa and IIb elicit three dose-dependent stages of electrocortical changes (trains of slow waves, trains of spike-and-wave complexes and "grand-mal" seizures). Compounds Ic, Id and Ig elicit only the first two stages. Compound Ih elicits only the first stage. While compound Ie does not affect the EEG pattern, its 9-acetyl derivative If induces changes (cortical spindles and disruption of the hippocampal theta waves) characteristic of agonist ligands of BDZ receptor. These findings confirm that the efficacy of compounds DMCM, Ia, Ic, Id, Ig and Ih as inverse agonists of BDZ receptor in the EEG paradigm parallels the reduction of their apparent binding affinity in the presence of GABA. The 9-acetylated compounds may be more inverse agonist in vivo than predicted from the in vitro findings, due to hydrolysis in the plasma.
在兔子身上研究了3-甲氧基羰基-β-咔啉（β-CCM，Ia）、3-乙氧基羰基-β-咔啉（β-CCE，Ic）、3-丙氧基羰基-β-咔啉（PrCC，Ie）、3-N-甲基甲酰胺基-β-咔啉（FG-7142，Ig）以及2-乙酰基-3-甲氧基羰基-1,2-二氢-β-咔啉（IIa）及其相应的9-乙酰基衍生物（Ib、Id、If、Ih和IIb）的作用。此外，还研究了6,7-二甲氧基-4-乙基-3-甲氧基羰基-β-咔啉（DMCM）的作用。在体外研究中，这些药物在大脑皮层膜制剂中与3H-地西泮竞争苯二氮䓬（BDZ）受体。IC50值在纳摩尔范围内，乙酰基衍生物与其同类物之间无显著差异，只有化合物If与其同类物Ie相比，结合能力降低了10倍。在10^(-5)M GABA存在的情况下，观察到DMCM、Ia、Ic和Ig的结合能力降低，而If的结合能力增加。体内研究表明，DMCM、Ia、Ib、IIa和IIb引发三个剂量依赖性的皮层电变化阶段（慢波串、棘波-慢波复合波串和“大发作”癫痫）。化合物Ic、Id和Ig仅引发前两个阶段。化合物Ih仅引发第一阶段。而化合物Ie不影响脑电图模式，其9-乙酰基衍生物If诱导出BDZ受体激动剂配体特有的变化（皮层纺锤波和海马θ波的破坏）。这些发现证实，在脑电图范式中，化合物DMCM、Ia、Ic、Id、Ig和Ih作为BDZ受体反向激动剂的效力与其在GABA存在下表观结合亲和力的降低程度平行。由于在血浆中水解，9-乙酰化化合物在体内可能比体外研究结果预测的更具反向激动剂活性。
