Martin B R, Compton D R, Semus S F, Lin S, Marciniak G, Grzybowska J, Charalambous A, Makriyannis A
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond 23298-0613.
Pharmacol Biochem Behav. 1993 Oct;46(2):295-301. doi: 10.1016/0091-3057(93)90356-x.
One aspect of cannabinoid structure-activity relationships (SARs) that has not been thoroughly investigated is the aromatic (A) ring. Although halogenation of the side chain enhances potency, our recent observation that iodination of the A ring also enhanced activity was surprising. The purpose of this investigation was to establish the steric and electrostatic requirements at these sites of the cannabinoid molecule via molecular modeling, while determining pharmacological activity. Molecular modeling was performed using the Tripos molecular mechanics force field and the semiempirical quantum mechanical package AM1. The Ki values for novel cannabinoids were determined in a [3H]CP-55,940 binding assay and ED50 values generated from four different evaluations in a mouse model. The present studies underscore the increase in potency produced by a dimethylheptyl (DMH) side chain. Trifluoro substitutions on the pentyl side chain, or bromination of the DMH side chain, had little effect on the pharmacological activity. Any substitution at the C4 position of the aryl ring resulted in a loss of activity, which appears to be due to steric hindrances. Nitro, but not iodo, substitution at the C2 position essentially produces an inactive analog, and the drastic alteration of the electrostatic potential appears to be responsible. The altered pharmacological profile of the 2-iodo analog seems to be related to an alteration in the highest occupied molecular orbital because there is no alteration in the electron density map compared to delta 8-tetrahydrocannibinol.
大麻素结构-活性关系（SARs）中一个尚未得到充分研究的方面是芳香（A）环。虽然侧链卤化可增强效力，但我们最近观察到A环碘化也能增强活性，这一发现令人惊讶。本研究的目的是通过分子建模确定大麻素分子这些位点的空间和静电要求，同时测定其药理活性。使用Tripos分子力学力场和半经验量子力学软件包AM1进行分子建模。通过[3H]CP-55,940结合试验确定新型大麻素的Ki值，并在小鼠模型中通过四种不同评估得出ED50值。本研究强调了二甲基庚基（DMH）侧链导致的效力增加。戊基侧链上的三氟取代或DMH侧链的溴化对药理活性影响不大。芳环C4位的任何取代都会导致活性丧失，这似乎是由于空间位阻。C2位的硝基取代而非碘取代基本上产生无活性类似物，静电势的剧烈改变似乎是原因所在。2-碘类似物药理特性的改变似乎与最高占据分子轨道的改变有关，因为与δ8-四氢大麻酚相比，电子密度图没有变化。
