• Archives of Pharmacal Research
• /
• 제10권1호
• /
• pp.50-59
• /
• 1987

(E)-2-Phenylcyclopropylamine ((E)-TCP), (Z)-2-Phenylacyclopropylamine ((Z)-TCP), (E)-1-methyl-2-phenylcyclopropylamine ((E)-MTCP), and (Z)-1-methyl-2-phenylcyclopropylamine ((Z)-MTCP) were synthesized and used to determine to what extent 1-methylsubstitution and stereochemistry of 2-phenycyclopropylamines affect inhibition of monoamine oxidase (MAO). Inhibition of rat brain mitochondrial MAO-A and B by the compounds were measured using serotonin and benzylamine as the substrate, respectively and $IC_{50}$ values obtianed with 95% confidence limits by the method of computation. For the inhibition of MAO-A, (E)-MTPC ($IC_{50}$ = 6.2 * $10^{-8}$M) was found to be 37 times more potent than (Z)-MTCP ($IC_{50}$ = 7.8 * $10^{-8}$M), was 7 times more potent than (Z)-MTCP($IC_{50}$= 4.7 * $10^{-7}$M) and (E)-TCP($IC_{50}$ =7.8 * $10^{-8}$M),0.6 times as potent as (Z)- TCP ($IC_{50}$ = 4.4 * $10^{-8}$M). The results suggested that while without 1-methyl group, potency of a (Z)-isomer was comparable to that of (E)-isomer, the methyl group in its (Z)-position was very unfavorable to the inhibition of MAO and that in its (E)-position, the methyl group contributed positively to the potency as found by the fact that (E)-MTCP was 1-5 times more potent than (E)-TCP. In view of the selective inhibition of MAO-A- or B over MAO-A and 1-methyl substitution as well as the stereochemical factors did not significantly influence the selectivity.

• 대한약리학회지
• /
• 제20권2호
• /
• pp.73-80
• /
• 1984

본 연구에서는 higenamine과 그 유도체들이 백서 뇌 미토콘드리아 Monoamine Oxidase(MAO) 의 활성에 미치는 영향에 관하여 관찰하였다. 시험한 화합물들 중에서 심장의 등장성 수축에는 효과를 나타내지 않는 methoxyhigenamine이 가장 5-hydroxytryptamine(5-HT)과 phenylethylamine(PEA)에 대한 MAO의 활성을 가역적으로 억제시켰으며, 그 억제 양상은 각각 pure competitive형과 hyperbolic mixed 형이었다. 이에 5-HT에 대한 $IC_{50}$ 는 PEA에 대한 것보다 10배 정도 낮아서 MAO-B 보다는 MAO-A에서 더 강한 억제 작용을 나타내었다. 이로써 methoxyhigenamine은 가역적이며 비교적 MAO-A에 대해 선택적인 MAO 억제제로 사료된다.

• Archives of Pharmacal Research
• /
• 제11권1호
• /
• pp.33-40
• /
• 1988

Two new nitro analogs of tranylcypromine, (E)-2-(p-nitrophenyl)cyclopropylamine ((E)-p-NTCP) and (E)-2-(m-nitrophenyl)cyclopropylamine ((E)-m-NTCP) were synthesized in order to examine the effect of aromatic nitro substitution on the MAO-inhibitory activity of 2-phenylcyclopropylamines. The compounds were obtained by treating t-butyl (E)-2-(p-nitrophenyl) cyclopropanecarbamate and t-butyl (E)-2-(m-nitrophenyl)cyclopropanecarbamate with p-toluenesulfonic acid in $CH_3$CN. Inhibitions of rat brain mitochondrial MAO-A and B by the compounds were examined using serotonin and benzylamine as the substrate at both in vitro and ex vivo levels. It was found from in vitro measurements that (E)-p-NTCP at $6.0{\times}10^{-5}M$ elicited merely 22.5% inhibition against MAO-B without any effect on MAO-A. In contrast, (E)-m-NTCP showed fair degrees of inhibitions of MAO-A and B with $IC_{50}$ values, $2.5{\times}10^{-7}M\;and\;1.4{\times}10^{-6}M$, respectively. It was also noted from (E)-m-NTCP that m-nitro substitution caused a shift of selectivity of the inhibition toward MAO-A. According to ex vivo measurements at 1.5, 3, 6, and 12 hr following the administration of a dose of 0.015 mmol/kg, i.p. to the rats, the inhibition percents of MAO-A by (E)-m-NTCP were 58.6, 63.7 63.6, and 46.6%, slightly lower than those observed by tranylcypromine. Whereas, (E)-m-NTCP at the same dose level did not show significant inhibitions against both MAO-A and MAO-B. Possible reasons for the difference in potencies between (E)-m-NTCP and (E)-p-NTCP were sought in relation to differing electron withdrawing effects of m- and p-substituents which will influence electron density of the side chain amino functions and the partitions.

• Radiation Oncology Journal
• /
• 제11권2호
• /
• pp.205-217
• /
• 1993

In order to evalute the effects of radiation on mammalian neuronal system, we have examined the effect of gamma-ray radiation on the monoamine oxidase (MAO) activity in monoaminergic neurons. Following the whole body irradiation, MAO activity in the rat brain was measured as well as in the liver for the comparative studies between the neuronal and nonneuronal system. The effects of some radiation protectors and sensitizers were also examined in addition to the $O_2$ effect. The results can be summarized as follows. 1) The MAO activity of rat brain was minimally affected by the radiation dose up to 1,700 cGy Radiation dose above 2,500 cGy inhibited the brain MAO activity by no less than $l0\%.$ MAO-A form was found to be particularly sensitive to radiation. The liver MAO was somewhat inhibited (by about $5\%$) but hardly dependent on the dose of radiation. 2) The inhibitory effect on the brain was initiated immediately by the radiation dose of 2,500 cGy. On the contrary, for the liver, the inhibitory effect became apparent only 2 days after irradiation. 3) Two days after a dose of 2,500 cGy, Vmax and Km of the brain mitochondrial MAO decreased. For liver, Vmax decreased while Km increased, which indicates the kinetic patterns for the neuronal and nonneruronal systems are not affected similarly by radiation. 4) The effect of several known radiation protectors and sensitizers on MAO activity was tested ut no definite results were obtained. The level of -SH group increased in some degree upon radiation but not by the compounds. 5) MAO activity was not affected by $O_2$ concentration, while an elevated level of lipid peroxidase was found under the same condition. The results described here indicate that characteristics of MAO, one of the most important central nervous system enzymes, are liable to radiation, which is partially differentiated from the liver MAO. Also indicated are that the -SH groups are hardly related to the effect of radiation but the production of the lipid peroxide seems to be somewhat correlated to the effect of radiation.

• 한국식품과학회지
• /
• 제29권1호
• /
• pp.156-160
• /
• 1997

식용버섯류들의 MAO 저해활성을 검색할 목적으로 몇가지 유기용매를 이용하여 추출분획을 조제하고 이들의 MAO에 대한 저해활성을 검색하였다. 검색된 3종 버섯류의 유기용매 추출물들은 영지버섯 bud의 $CHCl_3$ 층을 제외하고는 모두 MAO-A에 대한 저해활성이 나타나지 않았으나 영지 bud의 경우 $CHCl_3$ 층에서 비교적 강력한 MAO-A 저해활성을 나타내어 영지 bud의 항암활성이 영지의 항암활성과 비교하여 더욱 강력하다는 기존의 보고와 관련하여 아주 흥미로운 결과로 영지의 성분연구에 아주 중요한 단서를 제공해 줄 것으로 생각된다. 또한 검색된 3종 버섯류의 유기용매 추출물들은 영지 bud, 표고버섯의 EtOAc 층에서 각각 51.3, 55.9%로 역한 정도의 저해활성이 관찰되었으며 그 외의 다른 버섯류들에서는 전혀 MAO-B에 대한 저해활성이 확인되지 않았다. 또한 영지버섯의 경우, $CHCl_3$ 층, EtOAc 층, $H_2O$ 층 모두에서 아주 미약하나마 MAO-B에 대한 저해활성을 나타냈으나 영지 bud의 경우 $CHCl_3$ 층에서 전혀 MAO-B에 대한 저해활성을 나타내지 않고 EtOAc 층에서 약한 MAO-B에 대한 저해활성이 확인되어 MAO-A와 MAO-B에 대한 영지버섯의 작용성분이 다른 성분일 것으로 추측된다.

• Archives of Pharmacal Research
• /
• 제13권1호
• /
• pp.82-96
• /
• 1990

Ten (E)-and (Z)-isomers of 2-phenylcyclopropylamine (PCA), 1-Me PCA, 2-Me-PCA, N-Me-PCA, and N, N-diMe PCA and fifteen o-. m-, p- isomers of (E) PCA with substituents of Me, Cl, F, OMe, OH were synthesized in this laboratory and tested for the inhibition of rat brain mitochondrial MAO-A and MAO-B. The effects of substituents, their positions, and stereochemistry on the inhibition were assessed for the compounds with substituents at cyclopropyl and amino groups and QSAR analyses were performed using the potency data of ring-substituted compounds. The best correlated QSAR equations are as follows : pI$_{50}$ = 0.804 $\pi^2$-0.834 Blo-1.069 Blm + 0.334 Lp-1.709 HDp +7.897 (r = 0.945, s =0.211, F = 16.691, p = 0.000) for the inhibition of MAO-A;PI$_{50}$= 1.815$\pi$-0.825 $\pi^2$-1.203R + 0.900 Es$^2$ + 0.869 Es$^3$ + 0.796 Es$^4$-0.992 HDp + 0.562 HAo + 3.893 (r = 0.982, s =0.178, F = 23.351, p = 0.000) for the inhibition of MAO-B. Based on the potency difference between stereoisomers of cyclopropylamine-modified compounds and an QSAR cavity near para position, two hydrophobic carities interacting with Me group, a hydrophobic site near para position, and an amino group binding site and that in addition to the same two hydrophotic cavities, hydrophotic area, steric boundaries, hydrogen-acceptor site, and amino group binding site, another steric boundary near para position and a hydrogen donating site near ortho position constitute active sites of MAO-B.

• Archives of Pharmacal Research
• /
• 제9권2호
• /
• pp.99-110
• /
• 1986

In order to use for metabolic studies of tranylcypromine (TCP), TCP-phenyl-$d_{5}$ was synthesized via the intermediates, 3-benzoylpropionic acid-$d_{5}$ and trans-2-phenylcyclopropanecarboxylic acid-$d_{5}$ -TCP(0.22 mmole/kg) and its deuterated analog were administered s. c. to the rats and GC/MS analyses of the urines led to the detection of N-acetyltranylcypromine (ATCP) and glucuronide conjugate of phenyl-hydroxylated ATCP. MAO activities in rat brain were measured using serotonin as the substrate. In vitro $IC_{50}$ of ATCP was determined to be $10^{-3}M$. The inhibitions by ATCP were not dependent on the preincubation time and were reversed by washing sedimented mitochondrial pellets after the preincubation. In vivo MAO inhibitions at various times of 0.5, 1.5, 3, 6, 12, and 23 hr after the administration of 0.4 mmole/kg (i. p. ) of ATCP were found to be 0.13, 73, 90, 89, and 74 %, respectively. Similarly, the inhibition percents by 0.015 mmole/kg (i. p. ) of TCP were 94, 99, 95, 91, 71 and 49%. The results strongly suggest that deacetylated product of ATCP may account for its in vivo MAO inhibition. The relationship between the metabolism via phenyl-hydroxylation and the in vivo potency of TCP was examined by QSAR study and it was found that groupings discriminating between the compounds with p-substituents and those without them only ensure high correlations, suggesting that ring-hydroxylation which occurs at the para position in most of the compounds is a determining factor to the potency of TCP.

• Applied Biological Chemistry
• /
• 제42권2호
• /
• pp.166-169
• /
• 1999

두충잎으로부터 얻은 MeOH 추출물의 n-BuOH 분획으로부터 silica gel column chromatography를 반복하여 monoamine oxidase B (MAO-B) 억제 활성을 갖는 flavonoid 배당체를 분리하였다. 화합물의 화학구조를 스펙트럼 데이터의 해석과 산가수분해반응을 이용하여 $3-O-[{\beta}-D-glucopyranosyl\;(1{\rightarrow}2)\;{\beta}-D-xylopyranosyl]\;quercetin$으로 결정하였다. 이 화합물의 MAO-B 억제활성에 있어서의 $IC_{50}$ 값은 $8.05\;{\mu}mol/l$로 측정되었다.