In-vivo pharmacological evaluation of the CB1-receptor allosteric modulator Org-27569.
In-vivo pharmacological evaluation of the CB1-receptor allosteric modulator Org-27569.
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DOI：
10.1097/fbp.0000000000000027
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发表时间：
2014-04
影响因子：
1.6
通讯作者：
Lichtman AH
中科院分区：
文献类型：
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作者：
Gamage TF;Ignatowska-Jankowska BM;Wiley JL;Abdelrahman M;Trembleau L;Greig IR;Thakur GA;Tichkule R;Poklis J;Ross RA;Pertwee RG;Lichtman AH
已经在体外表征了CB 1受体的几种变构调节剂（AM），包括Org 27569，其增强[3 H] CP 55，940的CB 1特异性结合，但在几种生化测定中表现为不可逾越的CB 1受体拮抗剂。虽然越来越多的研究已经调查了这种不寻常的AM的分子作用，但尚不清楚这些作用是否会转化为整个动物。本研究的目的是确定Org 27569是否会在对CB 1正构激动剂和拮抗剂敏感的成熟小鼠行为测定中产生作用。与正构CB 1拮抗剂/反向激动剂利莫那班相似，Org 27569减少了食物摄入;然而，这种厌食作用独立于CB 1受体。Org 27569单独不引起CB 1介导的作用，并且在改变正构激动剂大麻素、CP 55、940和Δ9-四氢大麻酚的抗伤害感受、僵硬和体温过低作用方面缺乏效力。此外，在药物辨别范例中，它没有改变FAAH缺陷小鼠中anandamide或野生型小鼠中Δ9-四氢大麻酚的辨别刺激作用。这些发现质疑Org 27569作为“金标准”CB 1 AM的效用，并强调需要开发具有从分子水平转化为整个动物的药理学的CB 1 AM。
Several allosteric modulators (AMs) of the CB1 receptor have been characterized in vitro, including Org27569, which enhances CB1-specific binding of [3H]CP55,940, but behaves as an insurmountable CB1-receptor antagonist in several biochemical assays. Although a growing body of research has investigated the molecular actions of this unusual AM, it is unknown whether these actions translate to the whole animal. The purpose of the present study was to determine whether Org27569 would produce effects in well-established mouse behavioral assays sensitive to CB1 orthosteric agonists and antagonists. Similar to the orthosteric CB1 antagonist/inverse agonist rimonabant, Org27569 reduced food intake; however, this anorectic effect occurred independently of the CB1 receptor. Org27569 did not elicit CB1-mediated effects alone and lacked efficacy in altering antinociceptive, cataleptic, and hypothermic actions of the orthosteric agonists anandamide, CP55,940, and Δ9-tetrahydrocannabinol. Moreover, it did not alter the discriminative stimulus effects of anandamide in FAAH-deficient mice or Δ9-tetrahydrocannabinol in wild-type mice in the drug discrimination paradigm. These findings question the utility of Org27569 as a ‘gold standard’ CB1 AM and underscore the need for the development of CB1 AMs with pharmacology that translates from the molecular level to the whole animal.