SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF AMINO, AZIDO, AND NITROGEN-MUSTARD ANALOGS OF 10-SUBSTITUTED CANNABIDIOL AND 11-SUBSTITUTED OR 12-SUBSTITUTED DELTA-8-TETRAHYDROCANNABINOL
SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF AMINO, AZIDO, AND NITROGEN-MUSTARD ANALOGS OF 10-SUBSTITUTED CANNABIDIOL AND 11-SUBSTITUTED OR 12-SUBSTITUTED DELTA-8-TETRAHYDROCANNABINOL
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DOI：
10.1021/jm00167a025
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发表时间：
1990-05-01
影响因子：
7.3
通讯作者：
RAZDAN, RK
中科院分区：
文献类型：
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作者：
COMPTON, DR;LITTLE, PJ;RAZDAN, RK
描述了含有氨基、烷基氨基、叠氮基或N，N-双(2-氯乙基)氨基官能团的多种新型10-取代的大麻二酚(CBD)和11-或12-取代的Δ8-四氢大麻酚(Δ8-THC)类似物的合成，以及它们在小鼠中的药理学评价。这些类似物仅具有DELTA.9-THC的完整药理学活性谱的一部分，表明大麻素介导的自发运动活性的降低、体温过低、镇痛和/或强直症不需要同时产生，这可能表明存在不止一种作用机制。分别具有乙氨基、丙氨基或叠氮基官能团的 10 取代 CBD 类似物 3、4 和 5 被证明基本上没有活性，除了产生伴随毒性的中枢神经系统 (CNS) 抑制。毒性和CNS抑制可能是这些含氮化合物中的相关现象，因为Δ8-THC的12-氨基和12-乙氨基类似物(8和11)也被证明具有很强的毒性。在10mg/kg剂量的DELTA.8-THC的11-乙氨基类似物(9)下观察到抗伤害和低体温反应(不降低运动活动)，而需要50mg/kg剂量的氮芥11-[N，N-双(2-氯乙基)氨基]-DELTA.8-THC(12)才能产生任何可观察到的药理作用。当评估所选类似物的拮抗特性时，它们未能减弱Δ9-THC的作用。一些氮芥类似物在外周或直接中枢神经系统给药后能够产生最小的药理作用；然而，这些类似物也未能在施用后立即或24-48小时后减弱Δ9-THC的作用。
The synthesis of a variety of novel 10-substituted cannabidiol (CBD) and 11- or 12-substituted .DELTA.8-tetrahydrocannabinol (.DELTA.8-THC) analogues containing amino, alkylamino, azido, or a N,N-bis(2-chloroethyl)amino functional group is described, as well as their pharmacological evaluation in mice. These analogues, which possess only a portion of the full pharmacological spectrum of activity of .DELTA.9-THC, indicate that cannabinoid-mediated reduction of spontaneous locomotor activity, hypothermia, antinociception, and/or catalepsy need not be produced simultaneously, possibly suggesting the existence of more than one mechanism of action. The 10-substituted CBD analogues 3, 4, and 5 with an ethylamino, propylamino, or azido functional group, respectively, proved to be largely inactive, except for the production of central nervous system (CNS) depression concomitant with toxicity. Toxicity and CNS depression may be related phenomena in these nitrogenous compounds since 12-amino and 12-ethylamino analogues (8 and 11) of .DELTA.8-THC also proved to be very toxic. Antinociceptive and hypothermic responses (without reduction of motor activity) were observed at a dose of 10 mg/kg of the 11-ethylamino analogue (9) of .DELTA.8-THC, while a dose of 50 mg/kg of the nitrogen mustard 11-[N,N-bis(2-chloroethyl)amino]-.DELTA.8-THC (12) was necessary to produce any observable pharmacological effect. When selected analogues were evaluated for antagonistic properties, they failed to attenuate the effects of .DELTA.9-THC. Some nitrogen mustard analogues were capable of producing minimal pharmacological effects after either peripheral or direct CNS administration; however, these analogues also failed to attenuate the effects of .DELTA.9-THC either immediately after administration of 24-48 h later.