Walker Ellen A, Brown Edward K, Sterious Steven N
Department of Pharmaceutical Sciences, Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, PA 19140, USA.
Psychopharmacology (Berl). 2007 Aug;193(2):187-97. doi: 10.1007/s00213-007-0769-0. Epub 2007 Apr 1.
Although competitive antagonism experiments are critical tools in the classification of potential pharmacotherapies, no studies have quantitatively compared the potencies of 5-HT(2C) receptor antagonists using the Schild regression analysis in vivo.
To evaluate the behavioral effects of 5-HT(2C) receptor agonists and antagonists, a series of nonselective 5-HT(2C) receptor antagonists, the 5-HT(2A/2C) receptor antagonist ketanserin, the 5-HT(2B) receptor antagonist SB 204,741, the 5-HT(2B/2C) receptor antagonist SB 200,646, and the peripherally acting 5-HT(2C) receptor antagonist RS102,221 were evaluated for their capacity to competitively antagonize the agonists MK212, mCPP, or BW723C86 in rats.
Male Sprague-Dawley rats (N = 28) were trained to respond under a fixed ratio 10 schedule of food reinforcement. A multiple-trial, cumulative-dosing procedure was used to evaluate the capacity of the compounds to suppress response rates.
MK212, mCPP, and the 5-HT(2B) receptor agonist BW723C86 dose-dependently decreased response rates. Only metergoline, mianserin, and methysergide produced a dose-dependent antagonism of the rate-decreasing effects of both mCPP and MK212. Apparent pA(2) analysis indicated that metergoline, mianserin, and methysergide were approximately equipotent as antagonists overall. Metergoline and mianserin failed to block the rate-decreasing effects of BW723C86. Ketanserin, SB 200,646, SB 204,741, and RS102,221 failed to block either mCPP or MK212, suggesting that 5-HT(2A), 5-HT(2B), or peripheral 5-HT(2C) receptors do not play a primary role in the rate-decreasing effects of these two agonists.
Taken together, these antagonism profiles suggest that the agonists MK212 and mCPP produce their rate-decreasing effects through a combination of 5-HT receptors with the 5-HT(2C) receptor playing a prominent but not exclusive role.
尽管竞争性拮抗实验是潜在药物疗法分类的关键工具，但尚无研究在体内使用希尔德回归分析对5-HT(2C)受体拮抗剂的效价进行定量比较。
为评估5-HT(2C)受体激动剂和拮抗剂的行为效应，对一系列非选择性5-HT(2C)受体拮抗剂、5-HT(2A/2C)受体拮抗剂酮色林、5-HT(2B)受体拮抗剂SB 204,741、5-HT(2B/2C)受体拮抗剂SB 200,646以及外周作用的5-HT(2C)受体拮抗剂RS102,221在大鼠中竞争性拮抗激动剂MK212、mCPP或BW723C86的能力进行了评估。
雄性Sprague-Dawley大鼠（N = 28）接受训练，在固定比率10的食物强化程序下做出反应。采用多次试验、累积给药程序评估化合物抑制反应率的能力。
MK212、mCPP和5-HT(2B)受体激动剂BW723C86剂量依赖性地降低反应率。只有麦角新碱、米安色林和甲基麦角新碱对mCPP和MK212的降低率效应产生剂量依赖性拮抗作用。表观pA(2)分析表明，麦角新碱、米安色林和甲基麦角新碱作为拮抗剂总体上效价大致相当。麦角新碱和米安色林未能阻断BW723C86的降低率效应。酮色林、SB 200,646、SB 204,741和RS102,221未能阻断mCPP或MK212，这表明5-HT(2A)、5-HT(2B)或外周5-HT(2C)受体在这两种激动剂的降低率效应中不发挥主要作用。
综合来看，这些拮抗作用情况表明激动剂MK212和mCPP通过5-HT受体的组合产生其降低率效应，其中5-HT(2C)受体发挥突出但非唯一的作用。
