Price G W, Burton M J, Collin L J, Duckworth M, Gaster L, Göthert M, Jones B J, Roberts C, Watson J M, Middlemiss D N
Department of Neuroscience, SmithKline Beecham Pharmaceuticals, Harlow, Essex, UK.
Naunyn Schmiedebergs Arch Pharmacol. 1997 Sep;356(3):312-20. doi: 10.1007/pl00005056.
Despite only modest homology between h5-HT1B and h5-HT1D receptor amino acid sequences, these receptors display a remarkably similar pharmacology. To date there are few compounds which discriminate between these receptor subtypes and those with some degree of selectivity, such as ketanserin, have greater affinity for other 5-HT receptor subtypes. We now report on two compounds, SB-216641 (N-[3-(2-dimethylamino) ethoxy-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-carboxamide) and BRL-15572 3-[4-(3-chlorophenyl) piperazin-1-yl]-1,1-diphenyl-2-propanol), which display high affinity and selectivity for h5-HT1B and h5-HT1D receptors, respectively. In receptor binding studies on human receptors expressed in CHO cells, SB-216641 has high affinity (pKi = 9.0) for h5-HT1B receptors and has 25-fold lower affinity at h5-HT1D receptors. In contrast, BRL-15572 has 60-fold higher affinity for h5-HT1D (pKi = 7.9) than 5-HT1B receptors. Similar affinities for these compounds were determined on native tissue 5-HT1B receptors in guinea-pig striatum. Functional activities of SB-216641 and BRL-15572 were measured in a [35S]GTPgammaS binding assay and in a cAMP accumulation assay on recombinant h5-HT1B and h5-HT1D receptors. Both compounds were partial agonists in these high receptor expression systems, with potencies and selectivities which correlated with their receptor binding affinities. In the cAMP accumulation assay, results from pK(B) measurements on the compounds again correlated with receptor binding affinities (SB-216641, pK(B) = 9.3 and 7.3; BRL-15572, pK(B) = <6 and 7.1, for h5-HT1B and h5-HT1D receptors respectively). These compounds will be useful pharmacological agents to characterise 5-HT1B and 5-HT1D receptor mediated responses.
尽管人5-羟色胺1B（h5-HT1B）受体和人5-羟色胺1D（h5-HT1D）受体的氨基酸序列之间只有适度的同源性，但这些受体显示出非常相似的药理学特性。迄今为止，几乎没有化合物能够区分这些受体亚型，而那些具有一定程度选择性的化合物，如酮色林，对其他5-羟色胺（5-HT）受体亚型具有更高的亲和力。我们现在报告两种化合物，SB-216641（N-[3-(2-二甲基氨基)乙氧基-4-甲氧基苯基]-2'-甲基-4'-(5-甲基-1,2,4-恶二唑-3-基)-(1,1'-联苯)-4-甲酰胺）和BRL-15572（3-[4-(3-氯苯基)哌嗪-1-基]-1,1-二苯基-2-丙醇），它们分别对h5-HT1B和h5-HT1D受体表现出高亲和力和选择性。在对CHO细胞中表达的人受体进行的受体结合研究中，SB-216641对h5-HT1B受体具有高亲和力（pKi = 9.0），而对h5-HT1D受体的亲和力低25倍。相比之下，BRL-15572对h5-HT1D受体（pKi = 7.9）的亲和力比对5-HT1B受体高60倍。在豚鼠纹状体的天然组织5-HT1B受体上测定了这些化合物的类似亲和力。在重组h5-HT1B和h5-HT1D受体的[35S]GTPγS结合试验和cAMP积累试验中测量了SB-216641和BRL-15572的功能活性。在这些高受体表达系统中，这两种化合物都是部分激动剂，其效力和选择性与它们的受体结合亲和力相关。在cAMP积累试验中，对这些化合物的pK(B)测量结果再次与受体结合亲和力相关（对于h5-HT1B和h5-HT1D受体，SB-216641的pK(B)分别为9.3和7.3；BRL-15572的pK(B)分别为<6和7.1）。这些化合物将是用于表征5-HT1B和5-HT1D受体介导反应的有用药理试剂。
