Jim K, Bolger G T, Triggle D J, Lambriecht G
Can J Physiol Pharmacol. 1982 Dec;60(12):1707-14. doi: 10.1139/y82-249.
A series of muscarinic agonists (n = 18) derived from dioxolane, furan, piperidine, and thiacyclohexane ring structures which have a degree of conformational restraint have been examined in guinea pig ileal smooth muscle. Binding to muscarinic receptors was determined by competition with 3H-labelled (-)-quinuclidinyl benzilate. Agonist binding was characterized by shallow displacement curves and Hill coefficients (nH) of less than 1. Binding (K1) was resolved into high (K1) and low (K2) affinity components. Correlations between drug-receptor binding and pharmacological activity were examined. A good correlation was found between K1 and K2 (pK1 = 1.33 X pK2 - 0.1), suggesting that the structural requirements for binding at low and high affinity sites are similar. Good correlations also exist between pK1 and pD2 (pK1 = 0.63 X pD2 + 1.27, furans and dioxolanes; pK1 = 0.71 X pD2 + 1.30, piperidines and thiacyclohexanes) confirming that a pharmacologically potent agonist has a high binding affinity. Although K1 represents only an "average" binding affinity its correlation with pD2 is better than those between pK1 or pK2 and pD2. The significance of these several correlations is discussed and some general limitations to the correlation of binding and response data at pharmacological receptors are noted.
一系列由二氧戊环、呋喃、哌啶和硫杂环己烷环结构衍生而来且具有一定程度构象限制的毒蕈碱激动剂（n = 18）已在豚鼠回肠平滑肌中进行了研究。通过与3H标记的（-）-奎宁环基苯甲酸酯竞争来测定与毒蕈碱受体的结合。激动剂结合的特征是位移曲线较浅且希尔系数（nH）小于1。结合（K1）被解析为高亲和力（K1）和低亲和力（K2）成分。研究了药物-受体结合与药理活性之间的相关性。发现K1和K2之间存在良好的相关性（pK1 = 1.33×pK2 - 0.1），表明在低亲和力和高亲和力位点结合的结构要求相似。pK1和pD2之间也存在良好的相关性（对于呋喃和二氧戊环，pK1 = 0.63×pD2 + 1.27；对于哌啶和硫杂环己烷，pK1 = 0.71×pD2 + 1.30），证实了具有药理活性的激动剂具有高结合亲和力。尽管K1仅代表“平均”结合亲和力，但其与pD2的相关性优于pK1或pK2与pD2之间的相关性。讨论了这些几种相关性的意义，并指出了药理受体结合和反应数据相关性的一些一般局限性。
