The 5-HT3 agent N-(3-chlorophenyl)guanidine (MD-354) serves as a discriminative stimulus in rats and displays partial agonist character in a shrew emesis assay.
The 5-HT3 agent N-(3-chlorophenyl)guanidine (MD-354) serves as a discriminative stimulus in rats and displays partial agonist character in a shrew emesis assay.
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5-HT3 剂 N-(3-氯苯基)胍 (MD-354) 可作为大鼠的辨别刺激物，并在鼩鼱呕吐试验中显示出部分激动剂特征。
DOI：
10.1007/s002130000410
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发表时间：
2000
影响因子：
3.4
通讯作者：
Glennon,RA
中科院分区：
文献类型：
--
作者：
Dukat,M;Young,R;Darmani,NN;Ahmed,B;Glennon,RA
理由：有一些证据表明5-HT 3受体可能参与滥用兴奋剂的作用，尽管这些证据相互矛盾。大多数研究集中在5-HT 3拮抗剂的检查，这可能是由于缺乏高亲和力的5-HT 3激动剂，容易穿透血脑屏障。目的：N-（3-氯苯基）胍（MD-354）是我们实验室开发的一类新的5-HT 3配体的成员。我们以前已经证明，MD-354可以发挥激动剂的作用，现在进一步探讨这个action.Methods：大鼠（n=9）进行了训练，区分2毫克/公斤MD-354从盐水车辆在两个杠杆的药物歧视任务（VI-15的强化时间表）。评价了5-HT 3特性药物的作用。结果：各种具有5-HT 3激动剂特性的药物可替代MD-354的促吐和止吐作用（MD-354 ED50=0.5 mg/kg）：奎帕嗪（ED 50 =0.2 mg/kg），间氯苯双胍（mCPBG，ED_（50）=1.4 mg/kg）、2-甲基5-HT（ED_（50）=4.5 mg/kg）、1-（2-萘基）双胍（2-NBG，ED_（50）=1.9 mg/kg）和N-（2-萘基）胍（2-NG，ED_（50）=0.7 mg/kg）。训练剂量的MD-354与5-HT 3拮抗剂扎可必利和托烷司琼联合给药导致刺激拮抗作用（AD 50 =0.02 mg/kg）;然而，单独给药扎可必利产生81%的MD-354-适当应答（ED 50 =0.03 mg/kg）。MD-354显示在非常高的剂量下在鼩 鼱中产生催吐作用（即，40毫克/公斤）;结论：MD-354是一种5-HT_3激动剂，可能是一种具有部分激动活性的药物。
Rationale:There is some, albeit conflicting, evidence that 5-HT3receptors might be involved in the actions of abused stimulants. Most studies have focussed on examinations of 5-HT3antagonists; this might be due to a lack of high-affinity 5-HT3agonists that readily penetrate the blood-brain barrier.Objectives: N-(3-Chlorophenyl)guanidine (MD-354) is a member of a novel class of 5-HT3ligands developed in our laboratories. We have previously demonstrated that MD-354 can exert agonist effects and now further explore this action.Methods:Rats (n=9) were trained to discriminate 2 mg/kg MD-354 from saline vehicle in a two-lever drug discrimination task (VI-15 s schedule of reinforcement). The actions of agents with 5-HT3character were evaluated. The emetic and antiemetic actions of MD-354 were also examined using the shrew as test subject.Results:Various agents with demonstrated 5-HT3agonist properties substituted for the MD-354 stimulus (MD-354 ED50=0.5 mg/kg): quipazine (ED50=0.2 mg/kg),meta-chlorophenylbiguanide (mCPBG, ED50=1.4 mg/kg), 2-methyl 5-HT (ED50=4.5 mg/kg), 1-(2-naphthyl)biguanide (2-NBG, ED50=1.9 mg/kg), andN-(2-naphthyl)guanidine (2-NG, ED50=0.7 mg/kg). Administration of the training dose of MD-354 in combination with the 5-HT3antagonists zacopride and tropisetron resulted in stimulus antagonism (AD50=0.02 mg/kg); administered alone, however, zacopride engendered 81% MD-354-appropriate responding (ED50=0.03 mg/kg). MD-354 was shown to produce an emetic effect in the shrew at very high doses (i.e., 40 mg/kg); however, when administered in combination with cisplatin, MD-354 behaved as an antiemetic agent at 10 mg/kg.Conclusion:Taken together, the results indicate that MD-354 is a 5-HT3agonist and that it might be an agent with partial agonist activity.