Radiosynthesis of [11C]brofaromine, a potential tracer for imaging monoamine oxidase A
Simon M. AmetameyH.‐F. BeerIlonka GuentherAngelo AntoniniKlaus L. LeendersP. C. WaldmeierP. August Schubiger
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Keywords:
Radioligand
Radiosynthesis
Piperidine
Moclobemide
Monoamine oxidase A
Clorgyline
Monoamine oxidase B
Clorgyline
Monoamine oxidase B
Tyramine
Monoamine oxidase A
Oxidative deamination
Biogenic amine
Moclobemide
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Moclobemide
Clorgyline
Monoamine oxidase A
Monoamine oxidase B
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It has been reported that selective MAO-A inhibitors, clorgyline and brofaromine, but not the MAO-B inhibitors, deprenyl and pargyline, stimulated rat pineal melatonin synthesis in humans and animals. Recent studies, however, found no eflect of moclobemide, a selective MAO-A inhibitor, on human plasma melatonin levels. Present study found that in vitro moclobemide produced very weak stimulation of rat pineal NAT activity. However, in vivo moclobemide induced a significant increase of rat pineal NAS and melatonin content, and a dramatic decrease of 5-HIAA content (HPLC-fluorimetric procedure). Moclobemide's effect on melatonin and related indoles could be detected as early as 30 min after the injection and lasted, at least, for 2 h. The possible reasons for discrepancies between human and animal data are discussed.
Moclobemide
Clorgyline
Monoamine oxidase A
Pargyline
Monoamine oxidase B
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瞄准：开发高产量的屏蔽(HTS ) 为单音的胺氧化酶(毛) 的试金 A 和 MAO-B 禁止者。方法：一根荧光探针基于测量毛的方法 -- A 和 MAO-B 活动被建立并且优化与它的敏感，稳定性和特性评估了。包括在 384 井格式的酶来源，底层集中，孵化体积和反应时间的反应条件被优化达到敏感、低的肺结核病人目标。结果：处于优化条件，毛的动态参数 -- A 和 MAO-B 被获得。到毛的血清素的 K (m) 价值 -- A 是 1.66 micromol/L，当到 MAO-B 的本甲基胺的是 0.80 micromol/L 时。到毛的 clorgyline 的 IC (50 ) 价值 -- A 是 2.99 nmol/L，并且到 MAO-B 的 deprenyl 的是 7.04 nmol/L，匹配从传统的度谱的试金获得的那些。在测试样品之中，一混合物在毛上施加了禁止的效果 -- 有 IC (50 ) 的一项活动作为 0.13， 0.19，和 0.13 micromol/L 与 IC (50 ) 在 MAO-B 活动作为 0.36 micromol/L，和三混合物有禁止的效果。Z' 因素分别地在 MAO-A-inhibitor 和 MAO-B-inhibitor HTS 系统是 0.71+/-0.03 和 0.75+/-0.03。结论：确定的试金能很好被用于毛 -- 与高质量，精确和重制度屏蔽的 A 和 MAO-B 禁止者。
Clorgyline
Monoamine oxidase B
Monoamine oxidase A
Selegiline
Phenelzine
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SR 95191 [3-(2-morpholino-ethyl-amino)-4-cyano-6-phenylpyridazine] is a novel psychotropic drug which possesses the pharmacological properties of a selective, reversible type A monoamine oxidase inhibitor (MAOI). The MAOI activity of SR 95191 was examined in the rat brain, liver and duodenum and compared to that of clorgyline, harmaline, l-deprenyl, moclobemide and cimoxatone. In vitro, SR 95191 selectively inhibited MAO-A and was less potent than cimoxatone, clorgyline and harmaline, but was more potent than moclobemide. Ex vivo, SR 95191 also preferentially inhibited MAO-A in the brain and was 6 and 13 times less potent than cimoxatone and moclobemide, respectively. Like all MAO-A inhibitors, SR 95191 in vivo caused a dose-dependent increase in striatal 3-methoxytyramine, dopamine, serotonin and in hypothalamic norepinephrine contents. A concomitant decrease in deaminated metabolites was observed. SR 95191 inhibited peripheral MAO activity in liver and duodenum. In brain, liver and duodenum, MAO inhibition induced by SR 95191 was short-lasting. Repeated dosing for 14 days did not enhance MAO-A inhibition. Like all reversible MAOIs, SR 95191 antagonized the long-lasting MAO-A inhibition induced by clorgyline. Finally, SR 95191 did not affect monoamine uptake either in vitro or in vivo and did not interact in vitro with a variety of neurotransmitter or drug receptor sites. Based on these results it is postulated that SR 95191 is a selective and reversible type A MAOI of medium potency, which may be of therapeutic benefit in depressed patients.
Moclobemide
Clorgyline
Monoamine oxidase A
Harmaline
Pargyline
Monoamine oxidase B
Monoamine oxidase inhibitor
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Moclobemide
Clorgyline
Harmaline
Monoamine oxidase A
Monoamine oxidase B
Nitrendipine
Tyramine
Methamphetamine
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Monoamine oxidase (MAO) is an FAD-containing mitochondrial outer-membrane protein which catalyzes the degradation of several neurotransmitters in the central nervous system. The two subtypes of MAO, MAOA and MAOB, have similar primary sequences but different substrate and inhibitor specificities. The structure of human MAOB has recently been determined, but the structure of MAOA remains unknown. To clarify the mechanisms underlying their unique substrate and inhibitor recognition and thereby facilitate the development of new specific inhibitors to treat MAO-related neurological disorders, rat MAOA was crystallized in a complex with the specific inhibitor clorgyline. Diffraction data were collected to 3.2 A resolution. The crystal belongs to the space group P4(3)2(1)2, with unit-cell parameters a = b = 158.2, c = 258.4 A.
Clorgyline
Monoamine oxidase B
Monoamine oxidase A
Phenelzine
Transferase
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Inhibition of MAO activity was measured in rat brain homogenates using 5‐HT as MAO‐A substrate and phenylethylamine as MAO‐B substrate. Moclobemide rather selectively inhibited MAO‐A. Its inhibitory potency is rather low, like that of toloxatone, whereas clorgyline, harmaline, cimoxatone and brofaromine were all found to be at least 100 times more potent. Phenelzine, isocarboxazid and tranylcypromine were nonspecific, inhibiting MAO‐A and MAO‐B to about the same extent. The same drugs were also tested ex vivo. Here again moclobemide preferentially inhibited MAO‐A; it was equipotent to clorgyline and brofaromine in these tests, and 2–4 times as potent as cimoxatone and harmaline. Moclobemide is a relatively weak MAO‐A inhibitor in vitro and yet more potent in vivo than other reversible inhibitors, suggesting that the compound may be converted in vivo to an active form. Nevertheless, it has not been possible so far to identify activated derivatives, and recent findings that moclobemide markedly inhibits liver MAO‐A within 5 min of an intravenous injection strongly suggests that the compound itself is responsible for the inhibition.
Moclobemide
Clorgyline
Monoamine oxidase A
Tranylcypromine
Harmaline
Monoamine oxidase B
Ex vivo
Phenelzine
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Moclobemide
Clorgyline
Monoamine oxidase A
Monoamine oxidase B
Discontinuation
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