PDF(Pubmed)
Abstract：
Phytocannabinoids with seven-carbon alkyl chains (phorols) have gained a lot of attention, as they are commonly believed to be more potent versions of typical cannabinoids with shorter alkyl chains. At the time of this article, cannabidiphorol (CBDP) and tetrahydrocannabiphorol (THCP) can both be purchased in the North American market, even though their biological activities are nearly unknown. To investigate their relative potency, we conducted in vitro receptor-binding experiments with CBDP (cannabinoid CB1/CB2 receptor antagonism, serotonin 5HT-1A agonism, dopamine D2S (short form) agonism, and mu-opioid negative allosteric modulation) and compared the observed activity with that of CBD. To our knowledge, this is the first publication to investigate CBDP\'s receptor activity in vitro. A similar activity profile was observed for both CBD and CBDP, with the only notable difference at the CB2 receptor. Contrary to common expectations, CBD was found to be a slightly more potent CB2 antagonist than CBDP (p < 0.05). At the highest tested concentration, CBD demonstrated antagonist activity with a 33% maximum response of SR144528 (selective CB2 antagonist/inverse agonist). CBDP at the same concentration produced a weaker antagonist activity. A radioligand binding assay revealed that among cannabinoid and serotonin receptors, CB2 is likely the main biological target of CBDP. However, both CBD and CBDP were found to be significantly less potent than SR144528. The interaction of CBDP with the mu-opioid receptor (MOR) produced unexpected results. Although the cannabidiol family is considered to be a set of negative allosteric modulators (NAMs) of opioid receptors, we observed a significant increase in met-enkephalin-induced mu-opioid internalization when cells were incubated with 3 µM of CBDP and 1 µM met-enkephalin, a type of activity expected from positive allosteric modulators (PAMs). To provide a structural explanation for the observed PAM effect, we conducted molecular docking simulations. These simulations revealed the co-binding potential of CBDP (or CBD) and met-enkephalin to the MOR.
摘要：
具有七个碳烷基链的植物大麻素（醇）已经获得了很多关注，因为它们通常被认为是具有较短烷基链的典型大麻素的更有效版本。在这篇文章的时候,大麻酚（CBDP）和四氢大麻酚（THCP）都可以在北美市场购买，尽管它们的生物活性几乎是未知的。为了调查它们的相对效力，我们用CBDP（大麻素CB1/CB2受体拮抗作用，5-羟色胺5HT-1A激动，多巴胺D2S（短形式）激动，和mu-阿片负变构调制），并将观察到的活性与CBD的活性进行了比较。据我们所知,这是第一个在体外研究CBDP受体活性的出版物。CBD和CBDP均观察到类似的活性曲线，在CB2受体上唯一显着差异。与共同的期望相反,发现CBD是比CBDP稍微更有效的CB2拮抗剂(p<0.05)。在最高测试浓度下，CBD表现出拮抗剂活性,SR144528(选择性CB2拮抗剂/反向激动剂)的最大应答为33%。相同浓度的CBDP产生较弱的拮抗剂活性。放射性配体结合分析显示，在大麻素和5-羟色胺受体中，CB2可能是CBDP的主要生物学靶标。然而,发现CBD和CBDP的效力明显低于SR144528.CBDP与μ阿片受体（MOR）的相互作用产生了意想不到的结果。尽管大麻二酚家族被认为是一组阿片受体的负变构调节剂（NAMs），我们观察到当细胞与3µM的CBDP和1µM的met-enkephalin孵育时，met-enkephalin诱导的mu-阿片内化显著增加，从正变构调节剂（PAMs）预期的一种活性。为观察到的PAM效应提供结构解释，我们进行了分子对接模拟。这些模拟揭示了CBDP(或CBD)和met-脑啡肽与MOR的共结合潜力。
