ANTINOCICEPTIVE (AMINOALKYL)INDOLES
ANTINOCICEPTIVE (AMINOALKYL)INDOLES
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DOI：
10.1021/jm00107a034
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发表时间：
1991-03-01
影响因子：
7.3
通讯作者：
WARD, SJ
中科院分区：
文献类型：
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作者：
BELL, MR;DAMBRA, TE;WARD, SJ
（氨烷基）吲哚（AAI）衍生物普拉多林（1a）在体外和离体条件下可抑制小鼠脑微粒体中前列腺素（PG）的合成，并在几种啮齿动物试验中表现出抗伤害活性。 这类新的PG合成抑制剂的体外结构-活性关系研究揭示了在三个方面与芳基乙酸的对应关系：（1）“α-甲基化”引起PG抑制效力的增加，（2）（R）-α-甲基异构体比S异构体更有活性，（3）2-甲基衍生物的芳酰基构象与芳酰基及相关芳香乙酸衍生物的活性构象一致。 与在C-2处缺乏取代基的50所见的去屏蔽相比，普拉瓦多林的C-4氢的H-1 NMR化学位移表明普拉瓦多林的羰基位于C-2附近，但在50中位于C-4附近。 与1a的羰基的这种构象变化相关的是PG合成酶抑制活性的降低。 紫外光谱和差核Overhauser研究的结果与这些构象归属是一致的。 α-甲基衍生物的低的优二性比率和观察到侧链可以通过三个亚甲基基团延伸而不显著损失PG抑制效力表明，这类抑制剂与PG合成酶的活性位点的结合强度和选择性低于芳基乙酸。 发现两种AAI 1a和30代谢为相应的乙酸衍生物，这两种衍生物均抑制PG合成。 AAI的抗伤害感受活性与PG合成酶抑制活性相关的观察结果的例外是1-萘甲酰基衍生物67，因为它和它的乙酸代谢物74都不抑制PG合成。 然而，67在四种不同的啮齿动物试验中具有抗伤害性。 这种萘甲酰基衍生物，阿片类药物，也抑制电刺激收缩小鼠输精管（MVD）的准备。 然而，与阿片类药物不同，纳洛酮不能拮抗这种抑制作用。 确定了AAI的一个亚系列，其中67个是原型。 这些化合物缺乏PG合成酶抑制活性，但它们在MVD制剂中的抑制效力大致与它们在体内的抗伤害感受效力相关。 普拉瓦多林对MVD也有抑制作用。 因此，其抗伤害感受活性可能是其PG合成酶抑制效力和另一种抗伤害感受机制的结果，后者与其在MVD中的抑制效力相关。 证据的总结表明，这第二个抗伤害性机制与结合到最近的特点大麻素受体。
The (aminoalkyl)indole (AAI) derivative pravadoline (1a) inhibited prostaglandin (PG) synthesis in mouse brain microsomes in vitro and ex vivo and exhibited antinociceptive activity in several rodent assays. In vitro structure-activity relationship studies of this new class of PG synthesis inhibitors revealed a correspondence in three respects to those reported for the arylacetic acids: (1) ''alpha-methylation'' caused an increase in PG inhibitory potency, (2) the (R)-alpha-methyl isomer was more active than the S isomer, (3) the hypothesized aroyl group conformation of the 2-methyl derivatives corresponded to the proposed and reported ''active'' conformations of the aroyl and related aromatic acetic acid derivatives. The H-1 NMR chemical shift of the C-4 hydrogen of pravadoline in comparison to the deshielding seen with 50, which lacks a substituent at C-2, suggested that the carbonyl group of pravadoline is located near C-2 but is located near C-4 in 50. Associated with this conformational change of the carbonyl group of 1a is a diminution of PG synthetase inhibitory activity. The results of UV and difference nuclear Overhauser studies of the two compounds were consistent with these conformational assignments. The low eudismic ratios of the alpha-methyl derivatives and the observation that the side chain may be extended by three methylene groups without significant loss of PG inhibitory potency suggests that this class of inhibitors bound less strongly and less selectively to the active site of PG synthetase than do the arylacetic acids. Two AAIs, 1a and 30, were found to be metabolized to the corresponding acetic acid derivatives, both of which inhibited PG synthesis. An exception to the observation that the antinociceptive activity of the AAIs was associated with PG synthetase inhibitory activity was the 1-naphthoyl derivative 67 since neither it nor its acetic acid metabolite 74 inhibited PG synthesis. Yet 67 was antinociceptive in four different rodent assays. This naphthoyl derivative, like opioids, also inhibited electrically stimulated contractions in the mouse vas deferens (MVD) preparation. Unlike opioids, however, the inhibition was not antagonized by naloxone. A subseries of AAIs was identified, of which 67 was prototypic. These compounds lacked PG synthetase inhibitory activity, but their inhibitory potency in MVD preparations correlated roughly with their antinociceptive potency in vivo. Pravadoline was also inhibitory in the MVD. Its antinociceptive activity, therefore, may be a consequence of both its PG synthetase inhibitory potency and another antinociceptive mechanism, the latter associated with its inhibitory potency in the MVD. The evidence is summarized which suggests that this second antinociceptive mechanism is associated with binding to the recently characterized cannabinoid receptor.