Hudkins R L, DeHaven-Hudkins D L, Stubbins J F
Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0540.
J Med Chem. 1991 Oct;34(10):2984-9. doi: 10.1021/jm00114a005.
Para-substituted analogues of the antimuscarinic agent caramiphen were synthesized and evaluated for their ability to bind to the M1 and M2 subtypes of the muscarinic receptor. The purpose of the set was to look for a possible relationship in binding affinity or receptor subtype selectivity with aromatic substituent parameters such as Hammett's sigma or Hansch's pi values. It is felt this could be determined initially with only four properly chosen substituents. In this approach, substituents were chosen which have an extreme value for sigma and for pi, in a positive and negative direction, in all combinations. The substituents chosen for examination were amino (-sigma, -pi); 1-pyrrolidinyl (-sigma, +pi); 1-tetrazolyl (+sigma, -pi), and iodo (+sigma, +pi). It was determined in this research that caramiphen binds with high affinity (Ki = 1.2 nM) and is selective for the M1 over M2 muscarinic receptor subtype (26-fold). An examination of para-substitution reveals that compounds with electron-withdrawing (+sigma) substituents showed M1 selectivity, while the derivatives with electron-donating groups (-sigma) were nonselective in the binding assays. On the basis of this finding, the nitro and cyano derivatives were prepared and found to be M1 selective. The + sigma derivatives showed a decrease in M2 affinity while the p-nitro and p-iodo derivatives retained approximately equal affinity as caramiphen for the M1 site. The nitro- and iodocaramiphen derivatives were as potent (M1, Ki = 5.52 and 2.11 nM, respectively) and showed a greater selectivity of M1 over M2 binding than the M1 prototypical agent pirenzepine (M1, Ki = 5.21 nM).
合成了抗毒蕈碱药物卡拉美芬的对位取代类似物，并评估了它们与毒蕈碱受体M1和M2亚型结合的能力。该系列研究的目的是寻找结合亲和力或受体亚型选择性与芳香取代基参数（如哈米特σ值或汉施π值）之间的可能关系。认为最初仅用四个适当选择的取代基就能确定这种关系。在这种方法中，选择了在正负方向上σ值和π值具有极值的所有组合的取代基。选择用于研究的取代基为氨基（-σ，-π）；1-吡咯烷基（-σ，+π）；1-四唑基（+σ，-π）和碘（+σ，+π）。本研究确定卡拉美芬具有高亲和力（Ki = 1.2 nM），并且对M1毒蕈碱受体亚型的选择性高于M2（26倍）。对位取代的研究表明，具有吸电子（+σ）取代基的化合物表现出M1选择性，而具有供电子基团（-σ）的衍生物在结合试验中无选择性。基于这一发现，制备了硝基和氰基衍生物，发现它们具有M1选择性。+σ衍生物对M2的亲和力降低，而对硝基和对碘衍生物对M1位点的亲和力与卡拉美芬大致相当。硝基和碘代卡拉美芬衍生物同样有效（M1，Ki分别为5.52和2.11 nM），并且与M1原型药物哌仑西平（M1，Ki = 5.21 nM）相比表现出对M1结合的选择性高于M2。
