Novel 1',1'-chain substituted hexahydrocannabinols: 9β-hydroxy-3-(1-hexyl-cyclobut-1-yl)-hexahydrocannabinol (AM2389) a highly potent cannabinoid receptor 1 (CB1) agonist.
Novel 1',1'-chain substituted hexahydrocannabinols: 9β-hydroxy-3-(1-hexyl-cyclobut-1-yl)-hexahydrocannabinol (AM2389) a highly potent cannabinoid receptor 1 (CB1) agonist.
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DOI：
10.1021/jm100641g
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发表时间：
2010-10-14
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;Alapafuja SO;Papanastasiou I;Paronis CA;Shukla VG;Papahatjis DP;Bowman AL;Halikhedkar A;Han X;Makriyannis A
为了更详细地了解关键侧链大麻素药效团的结构要求，我们扩展了我们的SAR，以涵盖9-酮和9-羟基三环结构内的各种构象修饰侧链。在本文所描述的化合物中，那些在C1 '位置被环戊基环取代的七原子长侧链对CB1和CB2具有非常高的亲和力（0.97 nM<Ki<5.25 nM），对两种受体中的任何一种都没有偏好。然而，在C1 '位置上存在较小的环丁基导致与CB1具有最佳的亲和力和选择性相互作用。因此，两个C1 ' -环丁基类似物，即(6aR, 10aR)-3-（1-己基-环丁基-1-基）-6,6a,7,8,10,10 - a-六氢-1-羟基-6,6-二甲基- 9h -二苯并[b，d]吡喃-9- 1和(6aR, 9R, 10aR)-3-（1-己基-环丁基-1-基）-6a,7,8,9,10,10 - a-六氢-6,6-二甲基- 6h -二苯并[b，d]吡喃-1,9二醇（7e-β, AM2389）对CB1表现出非常高的亲和性（分别为0.84 nM和0.16 nM）和显著的选择性（分别为16倍和26倍）。化合物7e-β具有很高的体内和体外效力，作用时间相对较长。
In pursuit of a more detailed understanding of the structural requirements for the key side chain cannabinoid pharmacophore we have extended our SAR to cover a variety of conformationally modified side chains within the 9-keto and 9-hydroxyl tricyclic structures. Of the compounds described here, those with a seven-atom long side chain substituted with a cyclopentyl ring at C1′ position have very high affinities for both CB1 and CB2 (0.97 nM<Ki<5.25 nM), with no preference for either of the two receptors. However, presence of the smaller cyclobutyl group at C1′ position leads to an optimal affinity and selectivity interaction with CB1. Thus, two of the C1′-cyclobutyl analogs, namely, (6aR, 10aR)-3-(1-hexyl-cyclobut-1-yl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-one and (6aR, 9R, 10aR)-3-(1-hexyl-cyclobut-1-yl)-6a,7,8,9,10,10a-hexahydro-6,6-dimethyl-6H-dibenzo[b,d]pyran-1,9 diol (7e-β, AM2389), exhibited remarkably high affinities (0.84 nM and 0.16 nM respectively) and significant selectivities (16- and 26-fold respectively) for CB1. Compound 7e-β was found to exhibit exceptionally high in vitro and in vivo potency with a relatively long duration of action.
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影响因子：
2.9
作者：
DODD, PR;HARDY, JA;DELAUNOY, JP
通讯作者：
DELAUNOY, JP
影响因子：
64.8
作者：
MUNRO, S;THOMAS, KL;ABUSHAAR, M
通讯作者：
ABUSHAAR, M
影响因子：
5.8
作者：
Abood, ME;Ditto, KE;Tao, Q
通讯作者：
Tao, Q
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