Wiley J L, Compton D R, Gordon P M, Siegel C, Singer M, Dutta A, Lichtman A H, Balster R L, Razdan R K, Martin B R
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0613, USA.
Neuropharmacology. 1996;35(12):1793-804. doi: 10.1016/s0028-3908(96)00120-7.
delta 8-Tetrahydrocannabinol (delta 8-THC) is a naturally occurring cannabinoid with a characteristic pharmacological profile of in vivo effects. Previous studies have shown that modification of the structure of delta 8-THC by inclusion of a nitrogen-containing functional group alters this profile and may alkylate the cannabinoid receptor, similar to the manner in which beta-funaltrexamine (beta-FNA) alkylates the micro-opioid receptor. Two novel analogs of delta 8-THC were synthesized: a nitrogen mustard analog with a dimethylheptyl side chain (NM-delta 8-THC) and a cyano analog with a dimethylpentyl side chain (CY-delta 8-THC). Both analogs showed high affinity for brain cannabinoid receptors and when administered acutely, produced characteristic delta 9-THC-like effects in mice, including locomotor suppression, hypothermia, antinociception and catalepsy. CY-delta 8-THC shared discriminative stimulus effects with CP 55,940; for NM-delta 8-THC, these effects also occurred, but were delayed. Although both compounds attenuated the effects of delta 9-THC in the mouse behavioral tests, evaluation of potential antagonist effects of these compounds was complicated by the fact that two injections of delta 9-THC produced similar results, suggesting that acute tolerance or desensitization might account for the observations. NM-delta 8-THC, but not CY-delta 8-THC, attenuated the discriminative stimulus effects of CP 55,940 in rats several days following injection. Hence, addition of a nitrogen-containing functional group to a traditional cannabinoid structure does not eliminate agonist effects and may produce delayed attenuation of cannabinoid-induced pharmacological effects.
δ8 - 四氢大麻酚（δ8 - THC）是一种天然存在的大麻素，具有体内效应的特征性药理学特征。先前的研究表明，通过引入含氮官能团来修饰δ8 - THC的结构会改变这种特征，并且可能使大麻素受体烷基化，类似于β - 芬太尼（β - FNA）使微阿片受体烷基化的方式。合成了两种新型的δ8 - THC类似物：一种带有二甲基庚基侧链的氮芥类似物（NM - δ8 - THC）和一种带有二甲基戊基侧链的氰基类似物（CY - δ8 - THC）。这两种类似物对脑大麻素受体均显示出高亲和力，急性给药时，在小鼠中产生特征性的δ9 - THC样效应，包括运动抑制、体温过低、抗伤害感受和僵住症。CY - δ8 - THC与CP 55,940具有共同的辨别刺激效应；对于NM - δ8 - THC，这些效应也会出现，但有所延迟。尽管在小鼠行为测试中这两种化合物都减弱了δ9 - THC的效应，但由于两次注射δ9 - THC产生了相似的结果，这表明急性耐受性或脱敏可能是导致这些观察结果的原因，这使得评估这些化合物的潜在拮抗作用变得复杂。NM - δ8 - THC，但不是CY - δ8 - THC，在注射几天后减弱了大鼠中CP 55,940的辨别刺激效应。因此，在传统大麻素结构中添加含氮官能团不会消除激动剂效应，并且可能会导致大麻素诱导的药理效应出现延迟减弱。
