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首页> 外文期刊>Journal of Medicinal Chemistry >Potent cyano and carboxamido side-chain analogues of 1', 1'-dimethyl-delta8-tetrahydrocannabinol.
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Potent cyano and carboxamido side-chain analogues of 1', 1'-dimethyl-delta8-tetrahydrocannabinol.

机译：1'，1'-二甲基-delta8-四氢大麻酚的强效氰基和羧酰胺侧链类似物。

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摘要

The synthesis and pharmacological profile of several cyano (1a-e) and carboxamido (2a-h) side-chain-substituted analogues of 1', 1'-dimethyl-Delta8-THC are described. Commercially available cyano compound 3 was transformed to the resorcinol 6 in a three-step sequence. Condensation of 6 with p-menth-2-ene-1,8-diol formed the THC 7a which, with sodium cyanide/DMSO, gave 1b. Protection of the phenol in 7a as the MOM derivative provided the common intermediate 8 for the synthesis of 1a,c,e. Compound 1d was also synthesized from 7a via the aldehyde 9a. Base hydrolysis of 1b gave the acid 10 which, via its acid chloride and subsequent treatment with the appropriate amine, formed the target compounds 2a-h. The pharmacological profile indicated that the cyano analogues 1a-e had very high CB1 binding affinity (0.36-13 nM) and high in vivo potency as agonists. Two analogues (1a,b) had extremely high potency in the mouse tetrad tests. The dimethylcarboxamido analogue 2a showed a similar profile to 1a,b. The high potency was also retained in analogue 2c. In contrast the sulfonamide analogue 2d was unique as it had greater affinity than Delta9-THC, yet it was practically devoid of agonist effects. This study suggests that the incorporation of a cyano or an amide substituent in the side chain of Delta8-THC-DMH can enhance potency and can also lead to compounds with a unique profile which have high binding affinity and are practically devoid of agonist effects.
机译：描述了几种氰基（1a-e）和羧酰胺基（2a-h）1'，1'-二甲基-Delta8-THC侧链取代的类似物的合成和药理作用。以三步顺序将市售的氰基化合物3转化为间苯二酚6。 6与对-薄荷基-2-烯-1,8-二醇的缩合形成THC 7a，与氰化钠/ DMSO一起生成1b。 7a中作为MOM衍生物的苯酚的保护提供了合成1a，c，e的常用中间体8。化合物1d也经由醛9a由7a合成。 1b的碱水解得到酸10，它通过其酰氯和随后用适当的胺处理而形成目标化合物2a-h。药理学特征表明，氰基类似物1a-e具有非常高的CB1结合亲和力（0.36-13 nM）和高的体内激动剂效价。在小鼠四联体试验中，两种类似物（1a，b）具有极高的效力。二甲基甲酰胺基类似物2a显示出与1a，b类似的特征。在类似物2c中也保留了高效力。相反，磺酰胺类似物2d是独特的，因为它比Delta9-THC具有更高的亲和力，但实际上没有激动剂作用。这项研究表明，在Delta8-THC-DMH的侧链中引入氰基或酰胺取代基可以增强效价，并且还可以产生具有独特结合特性的化合物，该化合物具有高结合亲和力并且几乎没有激动作用。

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