Soskić V, Joksimović J
Institute for Biological Research Belgrade 11060 Yugoslavia.
Curr Med Chem. 1998 Dec;5(6):493-512.
Dopaminergic and serotonergic ligands are widely applied in the therapy of some severe diseases in humans connected to the malfunctioning of the corresponding membrane receptors within the CNS. However, no pharmaceuticals of this type with an ideal therapeutic index have been synthesized so far and there is a constant need of producing new dopaminergic/serotonergic ligands with improved properties especially with regard to undesirable side effects expressed after a prolonged therapy. Dopaminergic/serotonergic ratio turned out to be important for a fine tuning of pharmacological profile of new ligands. Employing a bioisosteric approach, we have synthesized numerous quinoxalinediones, benztriazoles, benzimidazoles and 2-substituted benzimidazoles as potential dopaminergic and/or mixed dopaminergic/serotonergic compounds. With this purpose, benzimidazole and its derivatives were incorporated into phenylethylamine, 3- and 4-substituted phenylethylpiperidine, 1-substituted 4-arylpiperazine and semirigid 2-aminotetralin frame and the resulting ligands were checked for the binding affinity at the D1 and D2 dopamine and 5-HT1A serotonin receptors in radioligand binding assays in vitro. Synaptosomal membranes prepared from bovine caudate nuclei and hippocampi served as a source of the dopamine and serotonin receptors, respectively. [3H]SCH 23390 (D1 receptor-selective), [3H]spiperone (D2 receptor-selective) and 8 OH [3H]DPAT (5-HT1A receptor-selective) were employed as radioligands in competition binding assays. Properties of substituents introduced into position 2 of benzimidazole ring, as well as the nature of the frame into which benzimidazole pharmacophore was incorporated have been shown to determine ligand binding affinity, mode of action and receptor preference, i.e. dopaminergic/serotonergic affinity ratio. Benzimidazolyl-2-thione and benztriazole derivatives were the most potent dopaminergic/serotonergic ligands. Molecular ab initio calculations of the electronic properties of pharmacophoric entities of the new ligands revealed different electron density distribution around the benzene ring in the active and inactive ligands. It can be assumed that this difference influences the properties of pi-pi interactions in a receptor-ligand complex. The results are discussed in comparison with the data of other authors working on similar topics.
多巴胺能和5-羟色胺能配体广泛应用于治疗人类与中枢神经系统内相应膜受体功能失调相关的一些严重疾病。然而，到目前为止尚未合成出具有理想治疗指数的此类药物，并且一直需要生产具有改进特性的新型多巴胺能/5-羟色胺能配体，特别是在长期治疗后出现的不良副作用方面。多巴胺能/5-羟色胺能比率对于微调新配体的药理学特性很重要。采用生物电子等排体方法，我们合成了许多喹喔啉二酮、苯并三唑、苯并咪唑和2-取代苯并咪唑作为潜在的多巴胺能和/或混合多巴胺能/5-羟色胺能化合物。为此，将苯并咪唑及其衍生物引入苯乙胺、3-和4-取代苯乙哌啶、1-取代4-芳基哌嗪和半刚性2-氨基四氢萘骨架中，并在体外放射性配体结合试验中检测所得配体对D1和D2多巴胺受体以及5-HT1A 5-羟色胺受体的结合亲和力。分别从牛尾状核和海马制备的突触体膜用作多巴胺和5-羟色胺受体的来源。[3H]SCH 23390（D1受体选择性）、[3H]螺哌隆（D2受体选择性）和8-OH [3H]DPAT（5-HT1A受体选择性）用作竞争结合试验中的放射性配体。已表明引入苯并咪唑环2位的取代基的性质以及引入苯并咪唑药效团的骨架的性质决定了配体的结合亲和力、作用模式和受体偏好，即多巴胺能/5-羟色胺能亲和力比率。苯并咪唑-2-硫酮和苯并三唑衍生物是最有效的多巴胺能/5-羟色胺能配体。对新配体药效团实体电子性质的分子从头计算揭示了活性和非活性配体中苯环周围不同的电子密度分布。可以假定这种差异影响受体-配体复合物中π-π相互作用的性质。将结果与从事类似主题研究的其他作者的数据进行了比较讨论。
