Gnanalingham K K, Hunter A J, Jenner P, Marsden C D
Parkinson's Disease Society Experimental Research Laboratories, King's College, London, U.K.
Biochem Pharmacol. 1995 May 11;49(9):1185-93. doi: 10.1016/0006-2952(95)00035-x.
The ability of benzazepine D-1 dopamine agonists with varying efficacies in stimulating adenylate cyclase and to induce contralateral circling was investigated in rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle. In the 6-hydroxydopamine lesioned rats, the benzazepines SKF 38393 (7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine), SKF 75670 (3-CH3 analogue), SKF 80723 (6-Br analogue), SKF 83959 (6-Cl, 3-CH3, 3'-CH3 analogue), SKF 83565 (6-Cl, 3-CH3, 3'-Cl analogue) and SKF 82958 (6-Cl, 3-C3H5 analogue), all produced contralateral circling. The rank order of efficacies (maximal effect, Emax) being, SKF 83565 = SKF 75670 = SKF 83959 = SKF 80723 > SKF 38393 >> SKF 82958. In striatal slices from the intact hemisphere, dopamine, SKF 82958, SKF 80723 and SKF 75670 stimulated adenylate cyclase activity. The rank order of efficacies being SKF 82958 (109%) = dopamine (100%) = SKF 80723 (98%) > SKF 75670 (72%). Although, SKF 38393 (67%), SKF 83565 (64%) and SKF 83959 (59%) tended to stimulate adenylate cyclase activity, this effect did not reach statistical significance. In the 6-hydroxydopamine lesioned hemisphere, basal levels of adenylate cyclase activity were lower (-25%) than in the intact hemisphere. The maximal stimulation of adenylate cyclase activity (expressed as % basal levels) produced by dopamine and the benzazepines in the denervated striatum was greater than observed in the intact striatum. The rank order of efficacies in the dopamine denervated striatum being SKF 82958 (124%) > SKF 80723 (109%) = dopamine (100%) > SKF 38393 (82%) = SKF 83959 (77%) = SKF 83565 (70%) > SKF 75670 (55%). Moreover, dopamine stimulated adenylate cyclase activity in the denervated striatum with greater potency than in the intact side. The ability of the benzazepine derivatives to induce circling in the 6-hydroxydopamine lesioned rat is consistent with the general increase in the efficacies of dopamine and benzazepine stimulated adenylate cyclase activity in the dopamine denervated striatum. However, the maximal effects for inducing circling and stimulating adenylate cyclase activity do not correspond (e.g. SKF 82958 and SKF 75670). This discrepancy may reflect the involvement of other factors including a behavioural role for extrastriatal D-1 dopamine receptors and/or transduction systems other than adenylate cyclase.
在内侧前脑束单侧6 - 羟基多巴胺损伤的大鼠中，研究了具有不同刺激腺苷酸环化酶效力和诱导对侧旋转能力的苯并氮杂卓D - 1多巴胺激动剂。在6 - 羟基多巴胺损伤的大鼠中，苯并氮杂卓SKF 38393（7,8 - 二羟基 - 1 - 苯基 - 2,3,4,5 - 四氢 - 1H - 3 - 苯并氮杂卓）、SKF 75670（3 - CH3类似物）、SKF 80723（6 - Br类似物）、SKF 83959（6 - Cl，3 - CH3，3'- CH3类似物）、SKF 83565（6 - Cl，3 - CH3，3'- Cl类似物）和SKF 82958（6 - Cl，3 - C3H5类似物）均产生对侧旋转。效力的排序（最大效应，Emax）为，SKF 83565 = SKF 75670 = SKF 83959 = SKF 80723 > SKF 38393 >> SKF 82958。在完整半球的纹状体切片中，多巴胺、SKF 82958、SKF 80723和SKF 75670刺激腺苷酸环化酶活性。效力的排序为SKF 82958（109%） = 多巴胺（100%） = SKF 8072（98%） > SKF 75670（72%）。虽然，SKF 38393（67%）、SKF 83565（64%）和SKF 83959（59%）倾向于刺激腺苷酸环化酶活性，但这种效应未达到统计学意义。在6 - 羟基多巴胺损伤的半球中，腺苷酸环化酶活性的基础水平比完整半球低（ - 25%）。多巴胺和苯并氮杂卓在去神经支配的纹状体中对腺苷酸环化酶活性的最大刺激（以基础水平的百分比表示）大于在完整纹状体中观察到的。在多巴胺去神经支配的纹状体中效力的排序为SKF 82958（124%） > SKF 80723（109%） = 多巴胺（100%） > SKF 38393（82%） = SKF 83959（77%） = SKF 83565（70%） > SKF 75670（55%）。此外，多巴胺在去神经支配的纹状体中刺激腺苷酸环化酶活性的效力比在完整侧更高。苯并氮杂卓衍生物在6 - 羟基多巴胺损伤大鼠中诱导旋转的能力与多巴胺和苯并氮杂卓在多巴胺去神经支配的纹状体中刺激腺苷酸环化酶活性的效力普遍增加一致。然而，诱导旋转和刺激腺苷酸环化酶活性的最大效应并不对应（例如SKF 82958和SKF 75670）。这种差异可能反映了其他因素的参与，包括纹状体以外的D - 1多巴胺受体和/或除腺苷酸环化酶以外的转导系统的行为作用。
