van Wijngaarden I, Kruse C G, van Hes R, van der Heyden J A, Tulp M T
Department of Medicinal Chemistry, Duphar Research Laboratories, Weesp, The Netherlands.
J Med Chem. 1987 Nov;30(11):2099-104. doi: 10.1021/jm00394a028.
2-Phenylpyrroles were synthesized as conformationally restricted analogues of the substituted benzamide sultopride and the butyrophenones haloperidol and fluanisone. Dopamine antagonistic activity is maintained if the 2-phenylpyrrole side chain is linked to the pharmacophoric N-ethylpyrrolidine moiety of sultopride or to the 4-substituted piperazine moiety of fluanisone but is lost if the 2-phenylpyrrole is combined with the 4-substituted piperidine moiety of haloperidol. The 2-phenylpyrrole analogue 1 of sultopride is in vitro 0.25 and in vivo 3 times as potent as the parent compound. Its binding to the dopamine D-2 receptors is, in analogy to the substituted benzamides, strongly sodium-dependent. The 2-(4-fluorophenyl)pyrrole analogue 5 of fluanisone is superior in vitro as well as in vivo to the corresponding benzamide 7 and the butyrophenone fluanisone. The increase in activity is not only due to a higher affinity for the D-2 receptors but also to an enhanced oral absorption (ratio po/ip = 4.5 vs 40 for the benzamide and 60 for fluanisone). Compound 5 is further characterized by a high selectivity for the D-2 receptors, in contrast to the benzamide and butyrophenone analogues (ratio D-2/alpha 1 = 60, 2.0, and 0.3, respectively). The binding to the D-2 receptors has little dependence on sodium. The 2-phenylpyrrole 5 shares with the benzamide 7 a low potential to induce catalepsy, which is in contrast to haloperidol. So, 5-(4-fluorophenyl)-2-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]pyrrole (5) is the prototype of a new class of sodium-independent dopamine D-2 antagonists, which may be particularly useful as potential antipsychotics with a low propensity to induce acute extrapyramidal side effects.
2-苯基吡咯被合成为取代苯甲酰胺舒托必利以及丁酰苯类药物氟哌利多和氟阿尼酮的构象受限类似物。如果2-苯基吡咯侧链与舒托必利的药效基团N-乙基吡咯烷部分相连，或者与氟阿尼酮的4-取代哌嗪部分相连，多巴胺拮抗活性得以保留，但如果2-苯基吡咯与氟哌啶醇的4-取代哌啶部分结合，则活性丧失。舒托必利的2-苯基吡咯类似物1在体外的效力是母体化合物的0.25倍，在体内是3倍。与取代苯甲酰胺类似，它与多巴胺D-2受体的结合强烈依赖于钠离子。氟阿尼酮的2-(4-氟苯基)吡咯类似物5在体外和体内均优于相应的苯甲酰胺7和丁酰苯类药物氟阿尼酮。活性的增加不仅归因于对D-2受体的更高亲和力，还归因于口服吸收的增强（口服/腹腔注射比率：苯甲酰胺为4.5，氟阿尼酮为40，而化合物5为60）。与苯甲酰胺和丁酰苯类类似物相比，化合物5的另一个特点是对D-2受体具有高选择性（D-2/α1比率分别为60、2.0和0.3）。其与D-2受体的结合对钠离子的依赖性很小。2-苯基吡咯5与苯甲酰胺7一样，诱发僵住症的可能性较低，这与氟哌啶醇不同。因此，5-(4-氟苯基)-2-[[4-(2-甲氧基苯基)-1-哌嗪基]甲基]吡咯（5）是一类新型的不依赖钠离子的多巴胺D-2拮抗剂的原型，作为潜在的抗精神病药物，其诱发急性锥体外系副作用的倾向较低，可能特别有用。
