Damjanoska K J, Muma N A, Zhang Y, D'Souza D N, Garcia F, Carrasco G A, Kindel G H, Haskins K A, Shankaran M, Petersen B R, Van De Kar L D
Department of Pharmacology and Experimental Therapeutics, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA.
J Pharmacol Exp Ther. 2003 Mar;304(3):1209-16. doi: 10.1124/jpet.102.043489.
The 5-hydroxytryptamine(2A) and (2C) (5-HT(2A) and 5-HT(2C)) receptors are so closely related that selective agonists have not been developed until recently with the advent of (S)-2-(chloro-5-fluoro-indol-l-yl)-1-methylethylamine fumarate (Ro 60-0175), a putatively selective 5-HT(2C) receptor agonist. In the present study, Ro 60-0175 was used to analyze the importance of 5-HT(2C) receptors in hormone secretion. Injection of Ro 60-0175 (5 mg/kg s.c.) produced a maximum increase in plasma levels of adrenocorticotrophic hormone, oxytocin, and prolactin at 15 min postinjection and a maximum increase in plasma corticosterone levels at 60 min postinjection. Ro 60-0175-mediated increases in plasma hormone levels were dose-dependent (corticosterone ED(50) = 2.43 mg/kg; oxytocin ED(50) = 4.19 mg/kg; and prolactin ED(50) = 4.03 mg/kg). To assess the role of 5-HT(2C) and 5-HT(2A) receptors in mediating the hormone responses to Ro 60-0175, rats were pretreated with the 5-HT(2C) antagonist 6-chloro-5-methyl-1-[2-(2-methylpyridyl-3-oxy)-pyrid-5-yl carbonyl] indoline (SB 242084) or 5-HT(2A) antagonists (+/-)-2,3-dimethoxyphenyl-1-[2-4-(piperidine)-methanol] (MDL 100,907) before injection of Ro 60-0175 (5 mg/kg s.c.). Neither SB 242084 (0.1, 0.5, 1, and 5 mg/kg i.p.) nor MDL 100,907 (1, 5, and 10 microg/kg s.c.) significantly inhibited the Ro 60-0175-induced increases in plasma hormone levels. The data suggest that Ro 60-0175 increases hormone secretion by mechanisms independent of the activation of 5-HT(2C) and/or 5-HT(2A) receptors and suggest that Ro 60-0175 is not a highly selective 5-HT(2C) receptor agonist.
5-羟色胺（2A）和（2C）（5-HT（2A）和5-HT（2C））受体密切相关，直到最近随着（S）-2-（氯-5-氟-吲哚-1-基）-1-甲基乙胺富马酸盐（Ro 60-0175）的出现才开发出选择性激动剂，Ro 60-0175被认为是一种选择性5-HT（2C）受体激动剂。在本研究中，使用Ro 60-0175来分析5-HT（2C）受体在激素分泌中的重要性。注射Ro 60-0175（5毫克/千克，皮下注射）后15分钟，促肾上腺皮质激素、催产素和催乳素的血浆水平达到最大增幅，注射后60分钟血浆皮质酮水平达到最大增幅。Ro 60-0175介导的血浆激素水平升高呈剂量依赖性（皮质酮ED50 = 2.43毫克/千克；催产素ED50 = 4.19毫克/千克；催乳素ED50 = 4.03毫克/千克）。为了评估5-HT（2C）和5-HT（2A）受体在介导对Ro 60-0175的激素反应中的作用，在注射Ro 60-0175（5毫克/千克，皮下注射）前，用5-HT（2C）拮抗剂6-氯-5-甲基-1-[2-（2-甲基吡啶-3-氧基）-吡啶-5-基羰基]吲哚啉（SB 242084）或5-HT（2A）拮抗剂（+/-）-2,3-二甲氧基苯基-1-[2-4-（哌啶）-甲醇]（MDL 100,907）对大鼠进行预处理。SB 242084（0.1、0.5、1和5毫克/千克，腹腔注射）和MDL 100,907（1、5和10微克/千克，皮下注射）均未显著抑制Ro 60-0175诱导的血浆激素水平升高。数据表明，Ro 60-0175通过独立于5-HT（2C）和/或5-HT（2A）受体激活的机制增加激素分泌，并且表明Ro 60-0175不是一种高度选择性的5-HT（2C）受体激动剂。
