Pharmacological characterization of in vivo properties of putative mixed 5-HT1A agonist/5-HT(2A/2C) antagonist anxiolytics. II. Drug discrimination and behavioral observation studies in rats.
Pharmacological characterization of in vivo properties of putative mixed 5-HT1A agonist/5-HT(2A/2C) antagonist anxiolytics. II. Drug discrimination and behavioral observation studies in rats.
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推定混合 5-HT1A 激动剂/5-HT(2A/2C) 拮抗剂抗焦虑药体内特性的药理学特征。
DOI：
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发表时间：
1997
影响因子：
3.5
通讯作者：
W. Koek
中科院分区：
文献类型：
--
作者：
M. Kleven;M. Assié;W. Koek
为了表征它们的体内5-羟色胺（5-HT）2A拮抗剂性质，假定的混合5-HT 1A激动剂/5-HT（2A，2C）拮抗剂的能力（N-（29-（4-（2-嘧啶基）-1-哌嗪基）乙基）三环（3.3.1.1（3，7））癸烷-1-甲酰胺（WY-50，324），（2-（4-（4，4-双（4-氟苯基）丁基）-1-哌嗪基）-3-吡啶甲酸盐酸盐（FG 5974），9，10-二脱氢-N-（2-丙炔基）-6-甲基麦角林-8b-甲酰胺（LEK-8804）和反式-1，3，4，a5，10 b-六氢10-甲氧基-4-丙基-2H-（1）苯并吡喃醇[3，4-B]吡啶（CGS 18102 A）对抗（+/-）-2，5-二甲氧基-4-碘安非他明（DOI）在大鼠中产生的头部抽搐和辨别刺激（DS）作用的效果与5-HT 2拮抗剂酮色林和利坦色林进行了比较，以及5-HT 1A激动剂8-羟基-2-（二正丙基氨基）四氢化萘（8-OH-DPAT）和丁螺环酮。所有这些化合物均产生DOI诱导的头部抽搐的剂量相关性降低;然而，用5-HT 1A拮抗剂N-[2-[4-（2-甲氧基苯基）-1-哌嗪基]乙基]-N-（2-吡啶基）环己烷甲酰胺（WAY-100635）预处理未能改变利坦色林、酮色林或CGS 18102 A减弱DOI诱导的头部抽搐的能力。相比之下，WAY-100635完全阻断8-OH-DPAT、丁螺环酮和WY-50，324的作用，并部分阻断LEK-8804的作用，表明5-HT 1A激动剂性质涉及除CGS 18102 A之外的所有混合化合物的作用。在训练区分DOI（0.63 mg/kg）和盐水的大鼠中，在两个杠杆，FR 10药物辨别范例中，酮色林，利坦色林和CGS 18102 A阻断了训练剂量的DS效应超过50%。相比之下，WY-50，324、FG 5974、LEK-8804、丁螺环酮和8-OH-DPAT在达到完全抑制反应的剂量时，未能产生超过33%的DOI DS效应阻断。体内5-HT 1A激动剂作用通过以下发现得到证实：相对选择性和混合的5-HT 1A激动剂产生“血清素综合征”的一种或多种要素，即，平体姿势，前爪踩踏，或下唇退缩，并产生高水平的药物杠杆选择在大鼠训练区分8-OH-DPAT（0.16 mg/kg）从盐水。由于DOI诱导的头部抽搐和DS效应被认为是由5-HT 2A受体介导的，因此结果表明，推定的混合化合物CGS 18102 A在体内具有显著的5-HT 2A拮抗剂特性，而WY-50，324，FG 5974和LEK-8804的5-HT 2A拮抗剂效应不能被清楚地鉴定。
To characterize their in vivo 5-hydroxytryptamine (5-HT)2A antagonist properties, the ability of the putative mixed 5-HT1A agonists/5-HT(2A,2C) antagonists (N-(29(4-(2-pyrimidinyl)-1-piperazinyl)ethyl)tricyclo(3.3.1.1(3,7) ) decane-1-carboxamide (WY-50,324), (2-(4-(4,4-bis(4-fluorophenyl)butyl)-1-piperazinyl)-3-pyridinecarboxy lic acid hydrochloride (FG5974), 9,10-didehydro-N-(2-propynyl)-6-methylergoline-8b-carboxamid e (LEK-8804) and trans-1,3,4,a5,10b-hexahydro10-methoxy-4-propyl-2H-(1)benzopyra nol[3,4-b]pyridine (CGS 18102A) to antagonize both head twitches and discriminative stimulus (DS) effects produced by (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) in rats were compared with those of the 5-HT2 antagonists ketanserin and ritanserin, and the 5-HT1A agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and buspirone. All of these compounds produced dose-related decreases in DOI-induced head twitches; however pretreatment with the 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xanecarboxamide (WAY-100635) failed to alter the ability of ritanserin, ketanserin or CGS 18102A to attenuate DOI-induced head twitches. In contrast, WAY-100635 completely blocked the effects of 8-OH-DPAT, buspirone and WY-50,324, and partially blocked the effects of LEK-8804, demonstrating that 5-HT1A agonist properties are involved in the effects of all of the mixed compounds except CGS 18102A. In rats trained to discriminate DOI (0.63 mg/kg) from saline in a two-lever, FR10 drug discrimination paradigm, ketanserin, ritanserin and CGS 18102A blocked the DS effects of the training dose by more than 50%. In contrast, WY-50,324, FG5974, LEK-8804, buspirone and 8-OH-DPAT, up to doses that completely suppressed responding, failed to produce more than a 33% blockade of the DS effects of DOI. In vivo 5-HT1A agonist effects were demonstrated by the finding that relatively selective- and mixed-5-HT1A agonists produced one or more elements of the "serotonin syndrome," i.e., flat-body posture, forepaw treading, or lower-lip retraction, and produced high levels of drug-lever selection in rats trained to discriminate 8-OH-DPAT (0.16 mg/kg) from saline. Because DOI-induced head twitches and DS effects are thought to be mediated by 5-HT2A receptors, the results demonstrate that the putative mixed compound, CGS 18102A has prominent 5-HT2A antagonist properties in vivo, whereas 5-HT2A antagonist effects of WY-50,324, FG5974 and LEK-8804 could not be clearly identified.
8-羟基-2-（二正丙氨基）四氢萘的生化基础研究。
影响因子：
5
作者：
Rabin,RA;Winter,JC
通讯作者：
Winter,JC
DOI：
--
发表时间：
1989
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
Gleeson,S;Ahlers,ST;Mansbach,RS;Foust,JM;Barrett,JE
通讯作者：
Barrett,JE