Pugsley T A, Davis M D, Akunne H C, MacKenzie R G, Shih Y H, Damsma G, Wikstrom H, Whetzel S Z, Georgic L M, Cooke L W
Department of Therapeutics, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Co., Ann Arbor, Michigan, USA.
J Pharmacol Exp Ther. 1995 Dec;275(3):1355-66.
The present study determined the biochemical and pharmacological effects of PD 128907 [R-(+)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H- [1]benzopyrano[4,3-b]-1,4-oxazin-9-ol], a dopamine (DA) receptor agonist that shows a preference for the human D3 receptor. In transfected Chinese hamster ovary cells (CHO K1), PD 128907 displaced [3H]spiperone in a biphasic fashion which fit best to a two-site model, generating Ki values of 20 and 6964 nM for the high- and low-affinity sites for the D2L receptors and 1.43 and 413 nM for the corresponding sites for the D3 receptors. Addition of sodium and the GTP analog Gpp(NH)p to both the D2L and D3 caused a modest reduction in the affinity of the compound suggestive of an agonist type action. In agonist binding ([3H]N-0437), PD 128907 exhibited an 18-fold selectivity for D3 versus D2L, a selectivity similar to that found with antagonist binding to the high-affinity sites. PD 128907 exhibited only weak affinity for D4.2 receptors (Ki = 169 nM). No significant affinity for a variety of other receptors was observed. PD 128907 stimulated cell division (measured by [3H]thymidine uptake) in CHO p-5 cells transfected with either D2L or D3 receptors exhibiting about a 6.3-fold greater potency in activating D3 as compared to D2L receptors. In vivo the compound was active in reducing DA synthesis both in normal and gamma-butyrolactone (GBL) treated rats; in the GBL model, the decrease was greater in the higher D3-expressing mesolimbic region as compared with striatum which has a lower expression of D3 receptors. PD 128907 decreased DA release (as measured by brain microdialysis) both in rat striatum, nucleus accumbens and medial frontal cortex, as well as in monkey putamen. Behaviorally PD 128907 decreased spontaneous locomotor activity (LMA) in rats at low doses, whereas at higher doses stimulatory effects were observed. PD 128907 at high doses reversed the reserpine-induced decrease in LMA and induced stereotypy in combination with the D1 agonist SKF 38393 indicating postsynaptic DA agonist actions. It is unclear which of the subtypes of DA receptors might be mediating the pharmacological effects of PD 128907. However, the present findings indicating that PD 128907 shows a preference for DA D3 over D2L and D4.2 receptors indicates that its action at low doses may be due to interaction with D3 receptors and at higher doses, with both D2 and D3 receptors.
本研究确定了PD 128907 [R-(+)-反式-3,4,4a,10b-四氢-4-丙基-2H,5H-[1]苯并吡喃并[4,3-b]-1,4-恶嗪-9-醇]的生化和药理作用，该化合物是一种对人D3受体具有选择性的多巴胺(DA)受体激动剂。在转染的中国仓鼠卵巢细胞(CHO K1)中，PD 128907以双相方式取代[3H]螺哌隆，最适合双位点模型，D2L受体高亲和力和低亲和力位点的Ki值分别为20和6964 nM，D3受体相应位点的Ki值分别为1.43和413 nM。向D2L和D3受体中添加钠和GTP类似物Gpp(NH)p会使该化合物的亲和力适度降低，提示其具有激动剂类型的作用。在激动剂结合实验([3H]N-0437)中，PD 128907对D3受体与D2L受体的选择性为18倍，与拮抗剂结合到高亲和力位点时的选择性相似。PD 128907对D4.2受体仅表现出弱亲和力(Ki = 169 nM)。未观察到对多种其他受体有明显亲和力。在用D2L或D3受体转染的CHO p-5细胞中，PD 128907刺激细胞分裂(通过[3H]胸苷摄取测量)，激活D3受体的效力比激活D2L受体高约6.3倍。在体内，该化合物在正常大鼠和经γ-丁内酯(GBL)处理的大鼠中均能有效降低DA合成；在GBL模型中，与D3受体表达较低的纹状体相比，在D3受体表达较高的中脑边缘区域，DA合成的减少幅度更大。PD 128907可降低大鼠纹状体、伏隔核和内侧前额叶皮质以及猴壳核中的DA释放(通过脑微透析测量)。在行为学上，低剂量的PD 128907可降低大鼠的自发运动活动(LMA)，而高剂量时则观察到刺激作用。高剂量的PD 128907可逆转利血平诱导的LMA降低，并与D1激动剂SKF 38393联合诱导刻板行为，表明其具有突触后DA激动剂作用。尚不清楚哪种DA受体亚型可能介导PD 128907的药理作用。然而，目前的研究结果表明，PD 128907对DA D3受体的选择性高于D2L和D4.2受体，这表明其低剂量时的作用可能是由于与D3受体相互作用，而高剂量时则与D2和D3受体均有相互作用。
