Millan M J, Bervoets K, Rivet J M, Widdowson P, Renouard A, Le Marouille-Girardon S, Gobert A
Department of Psychopharmacology, Centre de Recherches de Croissy, France.
J Pharmacol Exp Ther. 1994 Sep;270(3):958-72.
In this study, we attempted to identify of the subtype(s) of alpha-2 adrenergic receptor (AR) involved in the control of motor behavior, nociception and the hippocampal synthesis of noradrenaline (NA) in the rat. The high efficacy alpha-2 AR agonists, xylazine and UK 14,304 [5-bromo-6-[2-imidazolin-2-yl-amino]quinoxaline], inhibited striatal accumulation of L-dopa in rats pretreated with NSD 1015 (an inhibitor of aromatic amino acid-decarboxylase), elicited a loss of the righting reflex in rats, provoked ataxia in the rotarod test in mice and elicited antinociception in the writhing and hot-plate tests in mice. Guanfacine and guanabenz, agonists acting preferentially at rat alpha-2A (R alpha-2A)/human alpha-2A (H alpha-2A) AR, mimicked the antinociceptive and motor actions of xylazine and UK 14,304 and likewise inhibited NA synthesis. The preferential R alpha-2A/H alpha-2A AR antagonist, [2-(2H-(1-methyl-1, 3-dihydroisoindole)methyl)-4, 5-dihydro-imidazole (BRL 44408), enhanced hippocampal synthesis of NA and blocked the antinociceptive and motor effects of UK 14,304, xylazine, guanfacine and guanabenz. Similarly, fluparoxan and des-fluorofluparoxan, preferential antagonists at R alpha-2A AR as compared to H alpha-2A AR, were highly active. In contrast, the preferential alpha-2B/alpha-2C AR antagonists, ARC 239 [2-(2-(4-o-methoxyphenyl)piperazine-1-yl)-ethyl)-4,4-dimethyl-1,3- (2H,4H)-isoquinolinedione] prazosin, corynanthine, spiroxatrine and [1,2-dimethyl-2,3,9,13-betetrahydro-1H-dibenzo(c,f)- imidazo(1,5-a)azepine (BRL 41992)], as well as the preferential H alpha-2A AR antagonist, [2-(2,6-dimethoxyphenoxyethyl)- aminomethyl-1,4-benzodioxane] (WB 4101), were only weakly active. Based on the actions of a total of 16, structurally diverse alpha-2 AR antagonists, a correlation matrix was constructed. This revealed a strong correlation among the tests (median r = 0.82) and allowed for a comparison between drug potency in inhibiting these alpha-2 AR-mediated actions and affinity at various populations of alpha-2 AR subtypes (see companion paper). Correlations for potency in the two motor tests were pronounced with R alpha-2A sites (0.85), modest with H alpha-2A sites (0.60) and alpha-2B sites (0.58) and poor with alpha-2C sites (0.35). For the two antinociceptive tests, correlations were likewise pronounced with R alpha-2A sites (0.80) but less marked with H alpha-2A sites (0.73), alpha-2B sites (0.62) and alpha-2C sites (0.62).(ABSTRACT TRUNCATED AT 400 WORDS)
在本研究中，我们试图确定参与控制大鼠运动行为、痛觉感受以及海马去甲肾上腺素（NA）合成的α₂肾上腺素能受体（AR）亚型。高效α₂ AR激动剂赛拉嗪和UK 14,304 [5 - 溴 - 6 - [2 - 咪唑啉 - 2 - 基 - 氨基]喹喔啉]，可抑制经NSD 1015（一种芳香族氨基酸脱羧酶抑制剂）预处理的大鼠纹状体内L - 多巴的蓄积，能使大鼠翻正反射消失，在小鼠转棒试验中引发共济失调，并在小鼠扭体试验和热板试验中产生抗伤害感受作用。胍法辛和胍那苄是优先作用于大鼠α₂A（Rα₂A）/人α₂A（Hα₂A）AR的激动剂，可模拟赛拉嗪和UK 14,304的抗伤害感受和运动作用，同样也能抑制NA合成。优先作用于Rα₂A/Hα₂A AR的拮抗剂[2 - (2H - (1 - 甲基 - 1,3 - 二氢异吲哚)甲基) - 4,5 - 二氢 - 咪唑（BRL 44408）]，可增强海马NA的合成，并阻断UK 14,304、赛拉嗪、胍法辛和胍那苄的抗伤害感受及运动效应。同样，与Hα₂A AR相比优先作用于Rα₂A AR的氟哌罗生和去氟氟哌罗生也具有高活性。相比之下，优先作用于α₂B/α₂C AR的拮抗剂ARC 239 [2 - (2 - (4 - o - 甲氧基苯基)哌嗪 - 1 - 基) - 乙基] - 4,4 - 二甲基 - 1,3 - (2H,4H) - 异喹啉二酮]、哌唑嗪、育亨宾、螺沙群和[1,2 - 二甲基 - 2,3,9,13 - 四氢 - 1H - 二苯并(c,f) - 咪唑并(1,5 - a)氮杂卓（BRL 41992）]，以及优先作用于Hα₂A AR的拮抗剂[2 - (2,6 - 二甲氧基苯氧基乙基) - 氨基甲基 - 1,4 - 苯并二恶烷]（WB 4101），活性都较弱。基于总共16种结构各异的α₂ AR拮抗剂的作用，构建了一个相关矩阵。这揭示了各试验之间存在强相关性（中位数r = 0.82），并能够比较药物在抑制这些α₂ AR介导的作用方面的效力与对不同α₂ AR亚型群体的亲和力（见配套论文）。在两个运动试验中，效力与Rα₂A位点的相关性显著（0.85），与Hα₂A位点（0.60）和α₂B位点（0.58）的相关性中等，与α₂C位点（0.35）的相关性较差。对于两个抗伤害感受试验，与Rα₂A位点的相关性同样显著（0.80），但与Hα₂A位点（0.73）、α₂B位点（0.62）和α₂C位点（0.62）的相关性稍弱。（摘要截短于400字）
