O'Boyle K M, Gaitanopoulos D E, Brenner M, Waddington J L
Department of Clinical Pharmacology, Royal College of Surgeons, Dublin, Ireland.
Neuropharmacology. 1989 Apr;28(4):401-5. doi: 10.1016/0028-3908(89)90036-1.
Nine structurally related 1-phenyl-1H-3-benzazepine derivatives and two thienopyridines were tested for agonist and antagonist properties at the adenylate cyclase-coupled D1 dopamine receptor in homogenates of the striatum of the rat. The benzazepines SK&F 77434 and SK&F 82958, both of which contain a catechol ring, were agonists; the intrinsic activity of SK&F 77434 was similar to that of SK&F 38393, whereas SK&F 82958 was a full agonist. The remaining benzazepines inhibited the stimulation of adenylate cyclase by dopamine. Antagonist potency depended on the nature of the substituent at position 7 of the benzazepine molecule, 7-halogen compounds being the most potent. The Ki values, obtained from analysis of the antagonism of dopamine-stimulated adenylate cyclase, were significantly correlated with the Ki values for displacement of D1 ligands in binding experiments. Furthermore, antagonist activity of the resolved racemic benzazepine SK&F 83566 resided almost exclusively in the R-enantiomer. The thienopyridine derivatives SK&F 89641 and SK&F 89145 were partial agonists with greater efficacies than SK&F 38393.
对9种结构相关的1-苯基-1H-3-苯并氮杂卓衍生物和2种噻吩并吡啶进行了测试，以研究它们在大鼠纹状体匀浆中与腺苷酸环化酶偶联的D1多巴胺受体上的激动剂和拮抗剂特性。苯并氮杂卓类化合物SK&F 77434和SK&F 82958均含有儿茶酚环，它们是激动剂；SK&F 77434的内在活性与SK&F 38393相似，而SK&F 82958是完全激动剂。其余的苯并氮杂卓类化合物抑制多巴胺对腺苷酸环化酶的刺激作用。拮抗剂效力取决于苯并氮杂卓分子7位取代基的性质，7-卤素化合物最为有效。通过分析多巴胺刺激的腺苷酸环化酶的拮抗作用获得的Ki值，与结合实验中D1配体置换的Ki值显著相关。此外，拆分后的外消旋苯并氮杂卓SK&F 83566的拮抗活性几乎完全存在于R-对映体中。噻吩并吡啶衍生物SK&F 89641和SK&F 89145是部分激动剂，其效能高于SK&F 38393。
