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Novel cannabinol probes for CB1 and CB2 cannabinoid receptors

机译：CB1和CB2大麻素受体的新型大麻素探针

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The observation that the phenolic hydroxyl of THCs was important for binding to the CB1 receptor but not as critical for binding to the CB2 receptor prompted us to extend this finding to the cannabinol (CBN) series. To study the SAR of CBN analogues, CBN derivatives with substitution at the C-1, C-3, and C-9 positions were chosen since these positions have played a key role in the SAR of THCs. CBN-3-(1',1'-dimethylheptyl) analogues were prepared by sulfur dehydrogenation of Delta(8)-THC-3-(1',1'-dimethylheptyl) analogues. 9-Substituted CBN analogues were prepared by the standard sulfur dehydrogenation of B-substituted Delta(8)-THC analogues (Scheme 1), which in turn were prepared following our previous procedure using selenium dioxide oxidation of the corresponding Delta(8)-THCs followed by sodium chlorite oxidation to give the 9-carboxy-Delta(8)-THC derivatives. Il-Hydroxy-CBN analogues were prepared from the corresponding 9-carbomethoxy-CBN analogues by reduction with LiAlH4. Deoxy-CBN analogue 14 was prepared from the corresponding Delta(8)-THC analogue 11 by conversion of the phenolic hydroxyl to the phosphate derivative 12, followed by lithium ammonia reduction to provide the deoxy-as-THC analogue 13, which in turn was dehydrogenated with sulfur to provide the deoxy-CBN analogue 14 (Scheme 2). The various analogues were assayed for binding both to the brain and the peripheral cannabinoid receptors (CB1 and CB2). We have found that the binding profile differs widely between the CBN and the THC series. Specifically, in the CBN Series the removal of the phenolic hydroxyl decreases binding affinity to both the CB1 and CB2 receptors, whereas in the THC series, CB1 affinity is selectively reduced. Thus, in the CBN series, the selectivity of binding observed with the removal of the hydroxy group is decreased severalfold as compared to what occurs in the THC series. Generally, high affinity for the CB2 receptor was found in analogues when the phenolic hydroxyl was present. The 3-(1',1'-dimethylheptyl) derivatives were found to have much higher affinities than the CBN analogues, which is in complete agreement with previously reported work by Rhee et al(16). [References: 33]
机译：THCs的酚羟基对于与CB1受体结合很重要，但对与CB2受体结合却不那么重要的发现促使我们将这一发现扩展到大麻酚（CBN）系列。为了研究CBN类似物的SAR，选择了在C-1，C-3和C-9位置具有取代基的CBN衍生物，因为这些位置在THC的SAR中起着关键作用。 CBN-3-（1'，1'-二甲基庚基）类似物是通过Delta（8）-THC-3-（1'，1'-二甲基庚基）类似物的硫脱氢制备的。通过B取代的Delta（8）-THC类似物的标准硫脱氢反应制备了9位取代的CBN类似物（方案1），该步骤按照我们先前的步骤使用相应的Delta（8）-THC的二氧化硒氧化反应制备然后由亚氯酸钠氧化得到9-羧基-Delta（8）-THC衍生物。通过用LiAlH 4还原，由相应的9-羰甲氧基-CBN类似物制备II-羟基-CBN类似物。脱氧-CBN类似物14由相应的Delta（8）-THC类似物11制备，方法是将酚羟基转化为磷酸酯衍生物12，然后用氨水锂还原以提供脱氧-THC类似物13，用硫脱氢得到脱氧-CBN类似物14（方案2）。分析了各种类似物与大脑和外周大麻素受体（CB1和CB2）的结合。我们发现，CBN和THC系列之间的结合曲线差异很大。具体而言，在CBN系列中，酚羟基的去除会降低与CB1和CB2受体的结合亲和力，而在THC系列中，CB1亲和性会选择性降低。因此，在CBN系列中，与除去THC系列中发生的情况相比，观察到的除去羟基的结合的选择性降低了几倍。通常，当存在酚羟基时，在类似物中发现对CB2受体的高亲和力。发现3-（1'，1'-二甲基庚基）衍生物比CBN类似物具有更高的亲和力，这与Rhee等人（16）先前报道的工作完全一致。 [参考：33]

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