6"-Azidohex-2"-yne-cannabidiol:: a potential neutral, competitive cannabinoid CB1 receptor antagonist
6"-Azidohex-2"-yne-cannabidiol:: a potential neutral, competitive cannabinoid CB1 receptor antagonist
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DOI：
10.1016/j.ejphar.2004.01.023
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发表时间：
2004-03-08
影响因子：
5
通讯作者：
Pertwee, RG
中科院分区：
文献类型：
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作者：
Thomas, A;Ross, RA;Pertwee, RG
先前用小鼠输精管进行的实验表明，大麻二酚在远低于其与大麻素CB 1受体结合的浓度下产生大麻素CB 1受体激动剂的可克服的拮抗作用，并不可克服地拮抗α（1）-肾上腺素受体激动剂。它还增强了该组织的电诱发收缩。我们现在已经发现，大麻二酚结构的微妙变化显着影响其产生每种效果的能力，这表明这种非精神活性大麻素存在特定的药理学靶点。我们的实验用大麻二酚、6”-叠氮基己-2”-炔-大麻二酚、异常-大麻二酚和2-单甲氧基-和2 '，6'-二甲氧基-大麻二酚进行。其中，6”-叠氮基己-2”-炔-大麻二酚在输精管中产生（R）-（+）-[2，3-二氢-5-甲基-3-（4-吗啉基甲基）吡咯并-[1，2，3-de]-1，4-苯并恶嗪-6-基]-1-萘基甲酮（R-（+）-WIN 55212）的可克服的拮抗作用方面与大麻二酚一样有效。然而，它产生的这种拮抗作用与其大麻素CB 1受体亲和力相匹配，这表明，与大麻二酚不同，它是一种竞争性大麻素CB 1受体拮抗剂。此外，由于它不增加电诱发收缩的幅度，它可能是一种中性大麻素CB受体拮抗剂。(C)2004 Elsevier B. V.保留所有权利。
Previous experiments with the mouse vas deferens have shown that cannabidiol produces surmountable antagonism of cannabinoid CB1 receptor agonists at concentrations well below those at which it binds to cannabinoid CB1 receptors and antagonizes alpha(1)-adrenoceptor agonists insurmountably. It also enhances electrically evoked contractions of this tissue. We have now found that subtle changes in the structure of cannabidiol markedly influence its ability to produce each of these effects, suggesting the presence of specific pharmacological targets for this non-psychoactive cannabinoid. Our experiments were performed with cannabidiol, 6"-azidohex-2"-yne-cannabidiol, abnormal-cannabidiol and 2-monomethoxy- and 2',6'-dimethoxy-cannabidiol. Of these, 6"-azidohex-2"-yne-cannabidiol was as potent as cannabidiol in producing surmountable antagonism of (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo-[I,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (R-(+)-WIN55212) in vasa deferentia. However, it produced this antagonism with a potency that matched its cannabinoid CB1 receptor affinity, suggesting that, unlike cannabidiol, it is a competitive cannabinoid CB1 receptor antagonist. Moreover, since it did not enhance the amplitude of electrically evoked contractions, it may be a neutral cannabinoid CB, receptor antagonist. (C) 2004 Elsevier B.V. All rights reserved.