Herron D, Dillingham E O, Lyman B A, Zheng X, Bond S E, Salgia S R, Gollamudi R
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee, Memphis 38163, USA.
Prostaglandins Leukot Essent Fatty Acids. 1995 May;52(5):309-18. doi: 10.1016/0952-3278(95)90032-2.
Nipecotamides (piperidine-3-carboxamides) are potent inhibitors of platelet aggregation induced by a variety of agonists in vitro and in vivo. The inhibitory effects of six structural types of nipecotamides on human platelet aggregation induced by platelet-activating factor (PAF) in vitro, are studied. Evaluation of 15 racemates and stereoisomers of two nipecotamides showed that bis-nipecotoyl alkanes were more active than their mono congeners. Mono- and bis-nipecotoyl decanes were more potent than the corresponding hexanes. Lipophilicity was found to play a significant role in the antiplatelet activity of these compounds. The stereoselectivity in the PAF-antagonist potential of nipecotamides was less pronounced than that resulting from their action on ADP- or collagen-induced aggregation. Oxidation of the two benzylic carbon atoms of alpha, alpha'-bis[3-(N,N-diethylcarbamoyl)piperidino]-p-xylene.2HBr (A-1) to form 1,4-bis[3-N,N-diethylcarbamoyl) piperidino]benzenedicarboxamide (A-40K), which has a second set of carbonyl oxygens but lacks basic N atoms, resulted in a remarkable loss of ADP-antagonist potency while retaining PAF-antagonist activity. It is suggested that in addition to their membrane effects, nipecotamides act at other sites, including the PAF receptor. Double reciprocal plots of PAF binding to gel-filtered platelets (GFP) in the presence and absence of a typical nipecotamide (A-1C) were indicative of competitive inhibition (Ki = 19.28 microM). Scatchard analysis of 3H-PAF binding to GFP suggested the presence of high, intermediate (I) and low affinity binding sites, of which the I site gave a KD/app of 0.332 nM with an estimated 564 sites/platelet. Key interactions of nipecotamides with the PAF receptor appear to be the following (i) electrostatic interactions of the two amide oxygens with a primary set of electropositive areas spaced at 5-7 A, (ii) in the case of appropriate compounds, electrostatic interactions of the two amide oxygens spaced at 10-12 A with corresponding secondary receptor sites carrying positive electrostatic potential, (iii) a hydrophobic moiety fitting into a hydrophobic pocket in the receptor, and (iv) the cationic piperidine N+ (at pH 7.4) interacting with a counterion, probably aspartic acid.
氮杂环庚烷甲酰胺（哌啶-3-甲酰胺）在体外和体内都是多种激动剂诱导的血小板聚集的有效抑制剂。研究了六种结构类型的氮杂环庚烷甲酰胺对体外血小板活化因子（PAF）诱导的人血小板聚集的抑制作用。对两种氮杂环庚烷甲酰胺的15种外消旋体和立体异构体的评估表明，双氮杂环庚烷甲酰基烷烃比它们的单氮杂环庚烷甲酰基同系物更具活性。单氮杂环庚烷甲酰基和双氮杂环庚烷甲酰基癸烷比相应的己烷更有效。发现亲脂性在这些化合物的抗血小板活性中起重要作用。氮杂环庚烷甲酰胺的PAF拮抗剂潜力中的立体选择性不如其对ADP或胶原诱导的聚集作用所产生的立体选择性明显。α,α'-双[3-(N,N-二乙基氨基甲酰基)哌啶基]-对二甲苯·2HBr（A-1）的两个苄基碳原子氧化形成1,4-双[3-(N,N-二乙基氨基甲酰基)哌啶基]苯二甲酰胺（A-40K），后者有第二组羰基氧但缺少碱性N原子，导致ADP拮抗剂效力显著丧失，同时保留PAF拮抗剂活性。有人提出，除了它们的膜效应外，氮杂环庚烷甲酰胺还作用于其他位点，包括PAF受体。在存在和不存在典型氮杂环庚烷甲酰胺（A-1C）的情况下，PAF与凝胶过滤血小板（GFP）结合的双倒数图表明存在竞争性抑制（Ki = 19.28 microM）。3H-PAF与GFP结合的Scatchard分析表明存在高、中（I）和低亲和力结合位点，其中I位点的KD/app为0.332 nM，估计每个血小板有564个位点。氮杂环庚烷甲酰胺与PAF受体的关键相互作用似乎如下：（i）两个酰胺氧与一组间距为5-7 Å的主要正电区域的静电相互作用；（ii）对于合适的化合物，两个间距为10-12 Å的酰胺氧与带有正静电势的相应二级受体位点的静电相互作用；（iii）一个疏水部分嵌入受体中的疏水口袋；（iv）阳离子哌啶N+（在pH 7.4时）与一个抗衡离子相互作用，可能是天冬氨酸。
