Therapeutic potential and safety considerations for the clinical use of synthetic cannabinoids.
Therapeutic potential and safety considerations for the clinical use of synthetic cannabinoids.
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DOI：
10.1016/j.pbb.2020.173059
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Cooper ZD
中科院分区：
文献类型：
--
作者：
Sholler DJ;Huestis MA;Amendolara B;Vandrey R;Cooper ZD
植物大麻素Δ9-四氢大麻酚（THC）是在20世纪60年代分离和合成的。从那时起，基于临床安全性和有效性数据，靶向大麻素1（CB 1 R）和2（CB 2 R）受体的两种合成大麻素（SCB）被批准用于医疗用途：屈大麻酚（合成THC）和大麻隆（合成THC类似物）。为了进一步探索内源性大麻素系统的功能，开发了数百种研究化合物;特别是具有（1）相对于THC更大的CB 1/2 R亲和力和（2）完全CB 1/2 R激动剂活性的激动剂。相对于THC，这种药理学特征可能造成更大的误用和不良反应风险，并且这些SCB作为大麻的法律的替代品在零售市场上激增（例如，新的精神活性物质[1]，“香料”，“K2”）。这些SCB在美国基本上是非法的，但将所有SCB化学品纳入限制性控制类别的一揽子政策阻碍了SCB治疗开发新机制的研究进展。人们共同努力开发新的、治疗上有用的SCB，其靶向新的药理学机制。本综述强调了独特SCB的潜在疗效和安全性考虑，包括CB 1 R部分和完全激动剂，外周限制性CB 1 R激动剂，选择性CB 2 R激动剂，选择性CB 1 R拮抗剂/反向激动剂，CB 1 R变构调节剂，内源性大麻素降解酶抑制剂和大麻二酚。我们为SCB研究提出了有希望的方向，可以优化治疗效果并减少不良事件的可能性，例如，外周限制性CB 1 R拮抗剂/反向激动剂和偏向性CB 1/2 R激动剂。总之，这些策略可能会导致发现新的、治疗上有用的SCB，同时减少对公共卫生的负面影响。
The phytocannabinoid Δ9-tetrahydrocannabinol (THC) was isolated and synthesized in the 1960s. Since then, two synthetic cannabinoids (SCBs) targeting the cannabinoid 1 (CB1R) and 2 (CB2R) receptors were approved for medical use based on clinical safety and efficacy data: dronabinol (synthetic THC) and nabilone (synthetic THC analog). To probe the function of the endocannabinoid system further, hundreds of investigational compounds were developed; in particular, agonists with (1) greater CB1/2R affinity relative to THC and (2) full CB1/2R agonist activity. This pharmacological profile may pose greater risks for misuse and adverse effects relative to THC, and these SCBs proliferated in retail markets as legal alternatives to cannabis (e.g., novel psychoactive substances [NPS], “Spice,” “K2”). These SCBs were largely outlawed in the U.S., but blanket policies that placed all SCB chemicals into restrictive control categories impeded research progress into novel mechanisms for SCB therapeutic development. There is a concerted effort to develop new, therapeutically useful SCBs that target novel pharmacological mechanisms. This review highlights the potential therapeutic efficacy and safety considerations for unique SCBs, including CB1R partial and full agonists, peripherally-restricted CB1R agonists, selective CB2R agonists, selective CB1R antagonists/inverse agonists, CB1R allosteric modulators, endocannabinoid-degrading enzyme inhibitors, and cannabidiol. We propose promising directions for SCB research that may optimize therapeutic efficacy and diminish potential for adverse events, for example, peripherally-restricted CB1R antagonists/inverse agonists and biased CB1/2R agonists. Together, these strategies could lead to the discovery of new, therapeutically useful SCBs with reduced negative public health impact.
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