Moormann A E, Pitzele B S, Jones P H, Gullikson G W, Albin D, Yu S S, Bianchi R G, Sanguinetti E L, Rubin B, Grebner M
Preclinical Research, G. D. Searle and Company, Skokie, Illinois 60077.
J Med Chem. 1990 Feb;33(2):614-26. doi: 10.1021/jm00164a024.
Lofexidine, an alpha 2-agonist, has central hypotensive activity and peripheral intestinal antisecretory activity. Analogues were synthesized with increased polarity in an attempt to prevent penetration of the blood-brain barrier. The compounds were evaluated in the cholera toxin treated ligated jejunum of the rat and in the Ussing chamber with a rabbit ileum preparation. Active compounds were determined to be alpha 2-adrenergic agonists by yohimbine reversals of their Ussing chamber activities. The 2,6-dimethyl derivative of lofexidine, 4a, was as active as lofexidine in vivo, but derivatives with 2,6-substituents larger than ethyl were inactive. (Aryloxy)alkyl derivatives which have an imidazoline and a methyl or larger group as part of the alkyl exhibited the best antisecretory activity. Compounds with substituents in the para position of the phenyl ring were generally inactive. 3-Amino-2,6-dimethyl derivative 21 was twice as active as 4a. A 2-methyl substituent is required in the 3-amino series to retain good activity. 2-Methyl derivative 12a had activity comparable to that of 4a, while 6-methyl derivative 12f was inactive. Substituents on the 3-amino group did not affect the activity, but substituting a hydroxyl for the amino group produced an inactive compound. Replacing the phenyl moiety with a 4-indole resulted in retention of activity, but other heterocycles were inactive. Compound 12a was resolved and d isomer 32 was five times more potent than l isomer 33. The more active compounds in the rat cholera toxin assay (RCTA), when evaluated in the dog, exhibited antisecretory activity but also exhibited central nervous system (CNS) effects, sedation and ataxia, at 10 mg/kg, and in spontaneously hypertensive rats at 50 mg/kg. A measure of polarity, log P, was calculated for the (aryloxy)alkyl groups. Regression analysis showed no correlation of antisecretory ED50 to the calculated log P. The active compounds did not show a separation of the central CNS effects from the peripheral antisecretory activity by increasing the polarity.
洛非西定是一种α2激动剂，具有中枢性降压活性和外周肠道抗分泌活性。为防止血脑屏障穿透，合成了极性增加的类似物。这些化合物在霍乱毒素处理的大鼠结扎空肠以及用兔回肠制备的乌斯辛克小室中进行了评估。通过育亨宾对其在乌斯辛克小室中的活性进行逆转，确定活性化合物为α2肾上腺素能激动剂。洛非西定的2,6-二甲基衍生物4a在体内与洛非西定活性相当，但2,6-取代基大于乙基的衍生物无活性。具有咪唑啉且烷基部分有甲基或更大基团的（芳氧基）烷基衍生物表现出最佳的抗分泌活性。苯环对位有取代基的化合物通常无活性。3-氨基-2,6-二甲基衍生物21的活性是4a的两倍。在3-氨基系列中需要有2-甲基取代基以保持良好活性。2-甲基衍生物12a的活性与4a相当，而6-甲基衍生物12f无活性。3-氨基上的取代基不影响活性，但用羟基取代氨基会产生无活性的化合物。用4-吲哚取代苯基部分可保留活性，但其他杂环无活性。化合物12a被拆分，d异构体32的效力比l异构体33高五倍。在大鼠霍乱毒素试验（RCTA）中活性较高的化合物，在犬身上进行评估时，在10mg/kg剂量下表现出抗分泌活性，但也表现出中枢神经系统（CNS）效应、镇静和共济失调，在自发性高血压大鼠中在50mg/kg剂量下也有此表现。计算了（芳氧基）烷基的极性测量值log P。回归分析表明抗分泌ED50与计算出的log P无相关性。活性化合物未通过增加极性将中枢CNS效应与外周抗分泌活性区分开来。
