Probing the carboxyester side chain in controlled deactivation (-)-δ(8)-tetrahydrocannabinols.
Probing the carboxyester side chain in controlled deactivation (-)-δ(8)-tetrahydrocannabinols.
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DOI：
10.1021/jm501165d
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发表时间：
2015-01-22
影响因子：
7.3
通讯作者：
Makriyannis A
中科院分区：
文献类型：
--
作者：
Nikas SP;Sharma R;Paronis CA;Kulkarni S;Thakur GA;Hurst D;Wood JT;Gifford RS;Rajarshi G;Liu Y;Raghav JG;Guo JJ;Järbe TU;Reggio PH;Bergman J;Makriyannis A
我们最近报道了一种用于获得具有改善的可药用性的大麻素的受控失活/解毒方法。我们的设计在THC结构内的战略位置处结合了代谢不稳定的酯基。我们现在已经合成了一系列在3-烷基链中包含羧基酯基团的（−）-Δ8-THC类似物，以探索这种新型大麻能化学型的CB受体结合亲和力，体外和体内效力和功效，以及血浆酯酶的受控失活。我们还探讨了链的极性特性，快速起效和短时间的行动。我们的先导分子，即2-[（6aR，10aR）-6a，7，10，10a-四氢-1-羟基-6，6，9-三甲基-6H-二苯并[B，d]吡喃-3-基]-2-甲基-丙酸3-氰基-丙酯（AM 7438），显示出对CB受体的皮摩尔亲和力，并被血浆酯酶灭活，而相应的酸代谢产物无活性。在进一步的体外和体内实验中，发现该化合物是一种非常强效和有效的CB 1受体激动剂，具有相对快速的起效/抵消作用。
We recently reported on a controlled deactivation/detoxification approach for obtaining cannabinoids with improved druggability. Our design incorporates a metabolically labile ester group at strategic positions within the THC structure. We have now synthesized a series of (−)-Δ8-THC analogues encompassing a carboxyester group within the 3-alkyl chain in an effort to explore this novel cannabinergic chemotype for CB receptor binding affinity, in vitro and in vivo potency and efficacy, as well as controlled deactivation by plasma esterases. We have also probed the chain’s polar characteristics with regard to fast onset and short duration of action. Our lead molecule, namely 2-[(6aR,10aR)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-3-yl]-2-methyl-propanoic acid 3-cyano-propyl ester (AM7438), showed picomolar affinity for CB receptors and is deactivated by plasma esterases while the respective acid metabolite is inactive. In further in vitro and in vivo experiments, the compound was found to be a remarkably potent and efficacious CB1 receptor agonist with relatively fast onset/offset of action.
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影响因子：
64.8
作者：
MUNRO, S;THOMAS, KL;ABUSHAAR, M
通讯作者：
ABUSHAAR, M
DOI：
10.1039/b205459k
发表时间：
2002-01-01
期刊：
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1
影响因子：
--
作者：
Nikas, SP;Thakur, GA;Makriyannis, A
通讯作者：
Makriyannis, A
影响因子：
7.3
作者：
Dixon, Darryl D.;Sethumadhavan, Divakaramenon;Makriyannis, Alexandros
通讯作者：
Makriyannis, Alexandros
影响因子：
7.3
作者：
Durdagi, Serdar;Kapou, Agnes;Mavromoustakos, Thomas
通讯作者：
Mavromoustakos, Thomas
影响因子：
3.6
作者：
Kapur, Ankur;Hurst, Dow P.;Abood, Mary E.
通讯作者：
Abood, Mary E.