Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
Regional differences in the binding of selective muscarinic receptor antagonists in rat brain: comparison with minimum-energy conformations.
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大鼠脑中选择性毒蕈碱受体拮抗剂结合的区域差异：与最小能量构象的比较。
DOI：
10.1021/jm00126a004
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发表时间：
1989
影响因子：
7.3
通讯作者：
Hoss,W
中科院分区：
文献类型：
--
作者：
MesserJr,WS;Ellerbrock,BR;Smith,DA;Hoss,W
选择性毒蕈碱受体拮抗剂的结合，大鼠脑区域进行了检查，通过定量放射自显影技术。5，11-二氢-11-[（4-甲基-1-哌嗪基）乙酰基]-6R-吡啶并[2，3-b][1，4]苯并-二氮杂草-6-酮[哌仑西平（化合物I）]和II-[[2-[（二乙基氨基）甲基]-1-哌啶基]乙酰基]-5，11-二氢-6H-吡啶并[2，3-b][1，4]苯并二氮杂卓-6-酮[AF-DX 116（化合物II）]的选择是基于它们分别对M1和M2毒蕈碱受体的选择性以及化学结构的相似性。哌仑西平抑制[~ 3 H]-/-二苯羟乙酸奎宁环酯（[~ 3 H]-/-QNB）与大鼠脑切片结合的能力强于II。结合到脑切片的Scatchard分析揭示了两种拮抗剂的异质性结合特征，表明存在多个受体结合位点。定量放射自显影技术用于拮抗剂结合的区域分析。哌仑西平对海马、纹状体和杏仁核毒蕈碱受体的亲和力最高（IC 50值小于0.4 mM），对皮质受体的亲和力略低（IC 50值在0.4和0.8 mM之间）。哌仑西平对丘脑和脑干区域的亲和力最低，IC 50值通常大于1.0 mM。相比之下，II与脑干、小脑和下丘脑核中的毒蕈碱受体（IC 50值小于0.5 mM）的结合亲和力高于与丘脑核中的受体（IC 50值在0.5和2.0 mM之间）。在皮质、纹状体和海马区（IC 50值大于2.0 mM）发现对II亲和力最低的结合位点。两种选择性毒蕈碱拮抗剂的结合特征揭示了整个大脑中毒蕈碱受体亚型的复杂性和多样性。这些数据为用选择性配体鉴定毒蕈碱受体亚型（通过克隆程序定义）提供了基础。用MacroModel（2.0版）程序计算了哌仑西平和II的最小能量构象。哌仑西平显示三个能量最小值，不同的哌嗪环相对于三环系统的相对位置。与此相反，（二乙基氨基）甲基取代基上的哌啶环赋予了一个更大的最小能量构象II。这表明，侧链的构象灵活性更大，使II达到一个构象不可访问的哌仑西平，这使它能够优先结合到M2受体。
The binding of selective muscarinic receptor antagonists to regions of rat brain was examined through quantitative autoradiographic techniques. 5, ll-Dihydro-ll-[(4-methyl-l-piperazinyl) acetyl]-6R-pyrido [2, 3-6][l, 4] benzo-diazepin-6-one [pirenzepine (compound I)] and ll-[[2-[(diethylamino) methyl]-l-piperidinyl] acetyl]-5, ll-dihydro-6H-pyrido [2, 3-6][l, 4] benzodiazepin-6-one [AF-DX 116 (compound II)] were chosen on the basis of their selectivity for Mj and M2 muscarinic receptors, respectively, and similarities in chemical structure. Pirenzepine displayed a higher potency thanII for inhibition of [3H]-/-quinuclidinyl benzilate ([3H]-/-QNB) binding to rat brain sections. Scatchard analyses of binding to brain sections revealed heterogeneous binding profiles for both antagonists, suggesting the presence ofmultiple receptor binding sites. Quantitative autoradiographic techniques were utilized in regional analyses of antagonist binding. Pirenzepine displayed the highest affinity forhippocampal, striatal, and amygdaloid muscarinic receptors (IC50 values less than 0.4 mM), with a slightly lower affinity for cortical receptors (IC50 values between 0.4 and 0.8 mM). Pirenzepine displayed the lowest affinity for thalamic and brainstem regions with IC50 values generally greaterthan 1.0 mM. In contrast, II bound with higher affinity to muscarinic receptors in brainstem, cerebellar, and hypothalamic nuclei (IC50 values less than 0.5 mM) than to receptors in thalamic nuclei (ICm values between 0.5 and 2.0 mM). Binding sites with the lowest affinity for II were found in cortical, striatal, and hippocampal regions (IC50 values greater than 2.0 mM). The binding profiles of the two selective muscarinic antagonists reveal the complexity and diversity of muscarinic receptor subtypes throughout the brain. The data provide a basis for identifying muscarinicreceptor subtypes (as defined through cloning procedures) with selective ligands. Mini-mum-energy conformations of pirenzepine and II were calculated by using the program MacroModel (version 2.0). Pirenzepine displayed three energy minima, differing in the relative position of the piperazine ringwith respect to the tricyclic system. In contrast, the (diethylamino) methyl substituent on the piperidine ring conferred a much larger set of minimum-energy conformations on II. It is suggested that thegreater conformational flexibility of the side chain allows II to achieve a conformation inaccessible to pirenzepine, which allows it to bind preferentially to M2 receptors.