''Vinylogs'' and ''acetylenylogs'' of beta-adrenergic agents
''Vinylogs'' and ''acetylenylogs'' of beta-adrenergic agents
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DOI：
10.1002/ardp.19963290304
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发表时间：
1996-03-01
影响因子：
5.1
通讯作者：
Sulpizio, AC
中科院分区：
文献类型：
--
作者：
Nudelman, A;Binnes, Y;Sulpizio, AC
制备了经典的β-肾上腺素能药物兴奋剂和阻滞剂的乙烯基类(III组和V组)和乙酰基类似物(IV组)，以评价芳香环和含氨基官能团的链的饱和度、不饱和位置和刚性对生物活性的影响。来自第三族的衍生物代表了第二族的4-芳基-3-丁烯基-2-醇胺类似物，保持了β(1)-肾上腺素能受体拮抗剂的活性，尽管比它们的芳氧基化合物的效力低得多(50-200倍)。与II族化合物的SAR一致，芳环2位取代得到了最有效的拮抗剂(5a，5d，5g)，K-B为73-93 nM，而3，4-二氯取代(5e)显著降低了拮抗剂的效力(K-B=2400 nM)。5b和5d的激动剂活性也被注意到，这表明这些化合物最好被归类为部分激动剂。来自IV和V组的代表在β(1)-肾上腺素能受体上不作为拮抗剂，证实了羟基和氨基氮之间的空间关系的重要性。
Vinylogous (Groups III and V) and acetylenologous (Group IV) analogs of the classical beta-adrenergic agents - stimulants and blockers - were prepared in order to evaluate the effect of degree of saturation, position of unsaturation and rigidity of the chain linking the aromatic ring and the amino containing functional group on biological activity. Derivatives from Group III, which represent 4-aryl-3-butenyl-2-ol-amine analogs of Group II, retained beta(1)-adrenoceptor antagonist activity albeit substantially less potent (50-200-fold) than that possessed by their aryloxy counterparts. Consistent with the SAR for Group II compounds, substitution at position 2 of the aromatic ring yielded the most potent antagonists (5a, 5d, 5g), with K-B's ranging from 73-93 nM while 3,4-dichloro substitution (5e) markedly reduced antagonist potency (K-B = 2,400 nM). Agonist activity was also noted for 5b and 5d, suggesting that these compounds may be best classified as partial agonists. Representatives from Groups IV and V were inactive as antagonists at the beta(1)-adrenoceptor confirming the importance of the spatial relationship between the hydroxyl and the amino nitrogen.