Aloyo V J, Harvey J A
Department of Pharmacology and Physiology, MCP Hahnemann University, Mail Stop #488, 245 North 15th Street, 19102, Philadelphia, PA, USA.
Eur J Pharmacol. 2000 Oct 13;406(2):163-9. doi: 10.1016/s0014-2999(00)00645-2.
This study examined the binding of serotonin receptor antagonists at the 5-HT(2A) and 5-HT(2C) receptors of the rabbit's cerebral cortex. The 5-HT(2A) receptor was characterized by the binding of [3H]MDL 100,907 (R(+)-alpha-(2, 3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methan ol) to cortical membranes and the 5-HT(2C) receptor by the binding of [3H]mesulergine in the presence of the selective 5-HT(2A) receptor ligand spiperone. Both [3H]MDL 100,907 and [3H]mesulergine demonstrated high affinity binding to single sites in rabbit membranes. Based on Scatchard plots of [3H]MDL 100,907 binding, the mean B(max) was 8.5+/-0.7 fmol/mg tissue and the mean K(d) was 33. 1+/-3.5 pM. For [3H]mesulergine binding the mean B(max) was 3.70+/-0. 58 fmol/mg tissue and the mean K(d) was 0.35+/-0.05 nM. Binding of [3H]MDL 100,907 to the 5-HT(2A) receptor and of [3H]mesulergine to the 5-HT(2C) receptor was confirmed by displacement studies with highly selective 5-HT(2A) and 5-HT(2C) receptor ligands. The pharmacological profile of these ligands in rabbits correlated highly with published values for 5-HT(2A) (r=0.91, P<0.001) and 5-HT(2C) (r=0.94, P<0.001) receptors in humans. There was also a high correlation between the profiles for human and rat 5-HT(2C) receptor (r=0.92, P<0.001), but not for 5-HT(2A) receptors (r=0.53, P>0.10). It was concluded that the rabbit provides an appropriate animal model for studies attempting to predict the pharmacology of human 5-HT(2A) and 5-HT(2C) receptors.
本研究检测了5-羟色胺受体拮抗剂与兔大脑皮层5-HT(2A)和5-HT(2C)受体的结合情况。5-HT(2A)受体通过[3H]MDL 100,907（R(+)-α-(2,3-二甲氧基苯基)-1-[2-(4-氟苯基)乙基]-4-哌啶甲醇）与皮层膜的结合来表征，5-HT(2C)受体则通过在选择性5-HT(2A)受体配体螺哌隆存在的情况下[3H]美舒麦角的结合来表征。[3H]MDL 100,907和[3H]美舒麦角均显示出与兔膜中的单一位点有高亲和力结合。基于[3H]MDL 100,907结合的Scatchard图，平均最大结合量（B(max)）为8.5±0.7 fmol/mg组织，平均解离常数（K(d)）为33.1±3.5 pM。对于[3H]美舒麦角结合，平均B(max)为3.70±0.58 fmol/mg组织，平均K(d)为0.35±0.05 nM。通过用高选择性5-HT(2A)和5-HT(2C)受体配体进行置换研究，证实了[3H]MDL 100,907与5-HT(2A)受体以及[3H]美舒麦角与5-HT(2C)受体的结合。这些配体在兔中的药理学特征与已发表的人类5-HT(2A)（r = 0.91，P < 0.001）和5-HT(2C)（r = 0.94，P < 0.001）受体的值高度相关。人类和大鼠5-HT(2C)受体的特征之间也有高度相关性（r = 0.92，P < 0.001），但5-HT(2A)受体则不然（r = 0.53，P > 0.10）。得出的结论是，兔为试图预测人类5-HT(2A)和5-HT(2C)受体药理学的研究提供了合适的动物模型。
