The Synthesis and Pharmacological Evaluation of Adamantane-Derived Indoles: Cannabimimetic Drugs of Abuse
The Synthesis and Pharmacological Evaluation of Adamantane-Derived Indoles: Cannabimimetic Drugs of Abuse
复制标题
DOI：
10.1021/cn400035r
复制
发表时间：
2013-07-01
影响因子：
5
通讯作者：
Kassiou, Michael
中科院分区：
文献类型：
--
作者：
Banister, Samuel D.;Wilkinson, Shane M.;Kassiou, Michael
两个新的金刚烷衍生物金刚烷-1-酰基（1-戊基- 1h -吲哚-3-酰基）甲烷烯（AB-001）和N-（金刚烷-1-酰基）-1-戊基- 1h -吲哚-3-羧酰胺（db -001）最近被确定为滥用的大麻模拟吲哚。关于AB-001在人类中的精神活性的相互矛盾的轶事报道，以及关于SDB-001生物活性的信息的完全缺乏，促使了AB-001、SDB-001和一些类似物的制备，旨在探索这类药物的初步结构-活性关系。本研究旨在阐明AB-001、SDB-001及其类似物的哪些结构特征控制着这些化学型在体外和体内的拟大麻效力。使用FLIPR膜电位测定，所有化合物在CB1 （EC50 = 16-43 nM）和CB2 （EC50 = 29-216 nM）受体上显示出相似的完全激动剂特征，但SDB-002在CB2受体上显示出部分激动剂活性。采用生物遥测法将AB-001、AB-002和db -001与δ(9)-四氢大麻酚（δ (9)-THC）和拟大麻吲哚jwh018在大鼠体内的活性进行比较。SDB-001剂量依赖性诱导低温和降低心率（最大剂量10 mg/kg），其效价与Delta(9)-四氢大麻酚（Delta(9)-THC，最大剂量10 mg/kg）相当，低于JWH-018（最大剂量3 mg/kg）。此外，与Delta(9)-THC或JWH-018相比，SDB-001对体温和心率的影响持续时间更长，表明其药代动力学特征不同。相比之下，AB-001及其同系物AB-002即使在相对较高的剂量（高达30 mg/kg）下也不会产生显著的降体温和心动过缓作用，这表明与Delta(9)-THC、JWH-018和SDB-001相比，其效力大大降低。
Two novel adamantane derivatives, adamantan-1-yl (1-pentyl-1H-indo1-3-yl) methano ne (AB-001) and N-(adamtan-1-yl)-1-pentyl-1H-indole-3-carboxamide (SDB-001), were recently identified as cannabimimetic indoles of abuse. Conflicting anecdotal reports of the psychoactivity of AB-001 in humans, and a complete dearth of information about the bioactivity of SDB-001, prompted the preparation of AB-001, SDB-001, and several analogues intended to explore preliminary structure-activity relationships within this class. This study sought to elucidate which structural features of AB-001, SDB-001, and their analogues govern the cannabimimetic potency of these chemotypes in vitro and in vivo. All compounds showed similar full agonist profiles at CB1 (EC50 = 16-43 nM) and CB2 (EC50 = 29-216 nM) receptors in vitro using a FLIPR membrane potential assay, with the exception of SDB-002, which demonstrated partial agonist activity at CB2 receptors. The activity of AB-001, AB-002, and SDB-001 in rats was compared to that of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and cannabimimetic indole JWH-018 using biotelemetry. SDB-001 dose-dependently induced hypothermia and reduced heart rate (maximal dose 10 mg/kg) with potency comparable to that of Delta(9)-tetrahydrocannabinol (Delta(9)-THC, maximal dose 10 mg/kg), and lower than that of JWH-018 (maximal dose 3 mg/kg). Additionally, the changes in body temperature and heart rate affected by SDB-001 are of longer duration than those of Delta(9)-THC or JWH-018, suggesting a different pharmacokinetic profile. In contrast, AB-001, and its homologue, AB-002, did not produce significant hypothermic and bradycardic effects, even at relatively higher doses (up to 30 mg/kg), indicating greatly reduced potency compared to Delta(9)-THC, JWH-018, and SDB-001.