Agomelatine(S 20098) antagonizes the penile erections induced by the stimulation of 5-HT2C receptors in Wistar rats
Agomelatine(S 20098) antagonizes the penile erections induced by the stimulation of 5-HT2C receptors in Wistar rats
复制标题
DOI：
10.1007/s00213-003-1465-3
复制
发表时间：
2003-10-01
影响因子：
3.4
通讯作者：
Mocaër, E
中科院分区：
文献类型：
--
作者：
Chagraoui, A;Protais, P;Mocaër, E
阿戈美拉汀，一种具有褪黑激素激动剂和5-HT 2C拮抗剂特性的抗抑郁药，以及其两种主要代谢产物S 21517（N-[2-（7-羟基-1-萘基）乙基]乙酰胺）和S21540（N-[2-（3-羟基-7-甲氧基萘-1-基）乙基]乙酰胺），已经在猪脉络丛制备物上进行了体外评估，以确定它们对5-HT 2C受体的亲和力和它们对磷酸肌醇产生的影响。还测试了这些化合物抑制Wistar大鼠中由5-HT 2C受体激动剂间-（氯苯基）哌嗪（mCPP，0.75 mg/kg，SC）和Ro 60-0175（2.5 mg/kg，SC）诱导的阴茎勃起的能力。将这些体内效应与褪黑激素和5-HT拮抗剂吡唑替芬和SB 206，553的体内效应进行比较。阿戈美拉汀和S 21517对5-HT 2C受体具有中等亲和力，在体外表现为该受体亚型的弱拮抗剂。S 21540的亲和力低10倍。吡唑替芬和SB 206，553拮抗mCPP和Ro 60-0175诱导的阴茎勃起，表明mCPP或Ro 60-0175诱导的阴茎勃起是由5-HT 2C受体刺激引起的。褪黑激素剂量增加（1.25 - 40 mg/kg，IP）无法改变mCPP和Ro 60-0175诱导的阴茎勃起，阿戈美拉汀（1.25 - 40 mg/kg，IP）剂量依赖性降低mCPP和Ro 60-0175诱导的阴茎勃起。此外，阿戈美拉汀的两种主要代谢产物S 21517和S 21540的剂量增加（从1.25至40 mg/kg，IP）未影响mCPP和Ro 60-0175诱导的阴茎勃起。考虑到褪黑激素和阿戈美拉汀对褪黑激素受体的活性相似，这些数据表明，报告的效应不是由于褪黑激素受体的刺激，与褪黑激素相反，阿戈美拉汀除了对褪黑激素受体的激动剂活性外，还发挥5-HT 2C受体拮抗剂特性。最后，S 21517和S 21540似乎均未参与阿戈美拉汀对阴茎勃起的抑制作用。
Agomelatine, an antidepressant with melatonin agonist and 5-HT2C antagonist properties, as well as two of its main metabolites, S 21517 (N-[2-(7-hydroxy-1-naphtyl)ethyl]acetamide) and S21540 (N-[2-(3-hydroxy-7-methoxynaphtalen-1-yl)ethyl]acetamide), have been assessed in vitro on pig choroid plexus preparations to determine their affinities for 5-HT2C receptors and their effects on inositol phosphate production. These compounds were also tested for their ability to inhibit the penile erections induced by the 5-HT2C receptor agonists, m-(chlorophenyl)piperazine (mCPP, 0.75 mg/kg, SC) and Ro 60-0175 (2.5 mg/kg, SC) in Wistar rats. These in vivo effects were compared to those of melatonin and the 5-HT antagonists pizotifen and SB 206,553. Agomelatine and S 21517 had moderate affinity for 5-HT2C receptors and behaved in vitro as weak antagonists at this receptor subtype. S 21540 had a 10-fold lower affinity. Pizotifen and SB 206,553 antagonized mCPP- and Ro 60-0175-induced penile erections, suggesting that penile erections induced by mCPP or Ro 60-0175 resulted from the stimulation of 5-HT2C receptors. Whereas increasing doses (from 1.25 to 40 mg/kg, IP) of melatonin were unable to modify the penile erections induced by mCPP and Ro 60-0175, agomelatine (from 1.25 to 40 mg/kg, IP) dose-dependently decreased mCPP- as well Ro 60-0175-induced penile erections. Furthermore, increasing doses (from 1.25 to 40 mg/kg, IP) of S 21517 and S 21540, the two main metabolites of agomelatine, did not affect the penile erections induced by mCPP and Ro 60-0175. Considering the similar activity of melatonin and agomelatine at melatonin receptors, these data suggested that the reported effects were not due to the stimulation of melatonin receptors and that, contrary to melatonin, agomelatine exerted 5-HT2C receptor antagonist properties in addition to its agonist activity at melatonin receptors. Finally, neither S 21517 nor S 21540 seemed to participate to the observed inhibition of penile erections by agomelatine.