WAY-163909 [(7bR, 10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4]diazepino[6,7,1hi]indole]:: A novel 5-hydroxytryptamine 2C receptor-selective agonist with preclinical antipsychotic-like activity
WAY-163909 [(7bR, 10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta[b][1,4]diazepino[6,7,1hi]indole]:: A novel 5-hydroxytryptamine 2C receptor-selective agonist with preclinical antipsychotic-like activity
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DOI：
10.1124/jpet.106.106989
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发表时间：
2007-01-01
影响因子：
3.5
通讯作者：
Rosenzweig-Lipson, Sharon
中科院分区：
文献类型：
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作者：
Marquis, Karen L.;Sabb, Annmarie L.;Rosenzweig-Lipson, Sharon
5-羟色胺-2C（5-HT 2C）受体拮抗剂和激动剂已被证明影响多巴胺（DA）神经传递，激动剂选择性地降低中脑边缘DA。由于抗精神病药物的疗效被认为与借助于DA D2受体拮抗剂降低中脑边缘DA神经传递有关，因此5-HT 2C选择性受体激动剂WAY- 163909 [1]被认为是抗精神病药物的有效性的一种新的抑制剂。（7 bR，10 aR）-1，2，3，4，8，9，10，10 a-八氢-7bH-环戊二烯并-[ B][1，4]二氮杂卓并[6，7，1hi]吲哚]在精神分裂症动物模型和体内微透析和电生理学中进行评价，以确定对中脑边缘和黑质纹状体DA神经传递的影响。与氯氮平相似，WAY- 163909（1.7 - 30 mg/ kg i.第页）减少阿扑吗啡诱导的攀爬，对刻板症的影响很小，对僵硬症没有明显的诱导作用。WAY- 163909（0.3 - 3 mg/ kg s. c.）与对自发活动没有影响的D-安非他明相比，更有效地降低苯环己哌啶诱导的自发活动。WAY- 163909（1.7 - 17 mg/ kg i.第页）在DBA/2N小鼠中，逆转MK- 801（5 H二苯并[ a，d]环庚烯-5，10-亚胺（马来酸地佐环平））-和DOI [1-（2，5-二甲氧基-4-碘苯基）-2-氨基丙烷]-破坏惊吓（PPI）的前脉冲抑制，并改善PPI。WAY- 163909（0.3 - 3mg/ kg i. p.; 1 - 17 mg/ kg p.o.）回避反应减少，该作用可被5-HT 2B/2C受体拮抗剂SB 206553 [5-甲基-1-（3-吡啶基氨基甲酰基）-1，2，3，5-四氢吡咯并[ 2，3f]吲哚]阻断。WAY- 163909（10 mg/ kg s. c.）选择性地降低多巴胺的细胞外水平在脑桥核，而不影响纹状体。同样地，体内电生理记录显示在急性和慢性（21天）给予WAY 163909（1 - 10 mg/ kg i.）。因此，5-HT 2C选择性受体激动剂WAY- 163909的特征与非典型抗精神病药的特征相似，并且还可能具有快速起效的特性。
Serotonin-2C (5-HT2C) receptor antagonists and agonists have been shown to affect dopamine ( DA) neurotransmission, with agonists selectively decreasing mesolimbic DA. As antipsychotic efficacy is proposed to be associated with decreased mesolimbic DA neurotransmission by virtue of DA D 2 receptor antagonism, the 5-HT2C-selective receptor agonist, WAY- 163909 [( 7bR, 10aR)- 1,2, 3,4,8,9,10,10a- octahydro- 7bH- cyclopenta-[ b][ 1,4] diazepino[ 6,7, 1hi] indole], was evaluated in animal models of schizophrenia and in vivo microdialysis and electrophysiology to determine the effects on mesolimbic and nigrostriatal DA neurotransmission. Similar to clozapine, WAY- 163909 (1.7 - 30 mg/ kg i. p.) decreased apomorphine-induced climbing with little effect on stereotypy and no significant induction of catalepsy. WAY- 163909 (0.3 - 3 mg/ kg s. c.) more potently reduced phencyclidine-induced locomotor activity compared with d- amphetamine with no effect on spontaneous activity. WAY- 163909 (1.7 - 17 mg/ kg i. p.) reversed MK- 801 (5Hdibenzo[ a, d] cyclohepten-5,10- imine ( dizocilpine maleate)- and DOI [1-( 2,5- dimethoxy- 4- iodophenyl)-2-aminopropane]- disrupted prepulse inhibition of startle ( PPI) and improved PPI in DBA/2N mice. In conditioned avoidance responding, WAY- 163909 ( 0.3 - 3 mg/ kg i. p.; 1 - 17 mg/ kg p.o.) reduced avoidance responding, an effect blocked by the 5- HT2B/2C receptor antagonist SB 206553 [5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5- tetrahydropyrrolo[ 2,3f] indole]. WAY- 163909 ( 10 mg/ kg s. c.) selectively decreased extracellular levels of DA in the nucleus accumbens without affecting the striatum. Likewise, in vivo electrophysiological recordings showed a decrease in the number of spontaneously firing DA neurons in the ventral tegmental area but not in the substantia nigra with both acute and chronic(21-day) administration of WAY163909 ( 1 - 10 mg/ kg i. p.). Thus, the profile of the 5- HT2C selective receptor agonist WAY- 163909 is similar to that of an atypical antipsychotic and additionally may have rapid onset properties.