Structure-activity relationship studies on a novel series of (S)-2β-substituted 3α-[bis(4-fluoro- or 4-chlorophenyl)methoxy]tropane analogues for in vivo investigation
Structure-activity relationship studies on a novel series of (S)-2β-substituted 3α-[bis(4-fluoro- or 4-chlorophenyl)methoxy]tropane analogues for in vivo investigation
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DOI：
10.1021/jm060762q
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发表时间：
2006-10-19
影响因子：
7.3
通讯作者：
Newman, Amy Hauck
中科院分区：
文献类型：
--
作者：
Zou, Mu-Fa;Cao, Jianjing;Newman, Amy Hauck
一般来说，基于3 α-（二苯基甲氧基）托烷（苯托品）的多巴胺吸收抑制剂在精神兴奋剂滥用模型中没有表现出类似可卡因的药理活性，并已被提议作为治疗可卡因成瘾的潜在药物。然而，发现几种（S）-2-烷氧羰基取代的-3 α [双（4-氟苯基）甲氧基]托烷类似物在训练辨别可卡因的受试者中刺激自发活动和取代，表明2位取代基在介导这些可卡因样作用中的作用。在此，我们描述了一系列新的N-和2-取代的-3 α-[双（4-氟-或4-氯苯基）甲氧基]托烷类似物的合成。这些类似物中的大多数表现出与多巴胺转运蛋白（DAT; Ki = 1.8-40 nM）的高亲和力结合，以及对其他单胺转运蛋白和毒蕈碱M-1受体的选择性。当（S）-2-烷氧羰基取代基被（S）-2-乙烯基取代时，得到的类似物11表现出系列中最高的DAT结合亲和力（Ki = 1.81 nM），DAT选择性超过5-羟色胺转运蛋白（SERT; 989倍）、去甲肾上腺素转运蛋白（NET; 261倍）和毒蕈碱受体（90倍）。当化合物5的4 '-F基团（Ki = 2.94 nM）和8（Ki = 6.87 nM）被（S）-2-烷氧羰基系列中的4 '-Cl取代，DAT结合亲和力略微降低（对于6和7，Ki分别= 12.6和14.6 nM），但多巴胺摄取效力的抑制仍然很高（IC 50范围= 1.5-2.5 nM）。有趣的是，4 '-Cl类似物（+/-）-6在训练辨别可卡因的大鼠中的替代比4'-F类似物（+/-）-5少。这些研究表明，在3 α-（二苯基甲氧基）托烷类多巴胺摄取抑制剂中的2-，N-和3-位取代基的操作可以产生对DAT具有高亲和力和选择性的配体，以及无法通过其体外作用预测的独特的体内药理学特征。
In general, 3 alpha-(diphenylmethoxy)tropane (benztropine)-based dopamine uptake inhibitors do not demonstrate cocaine-like pharmacological activity in models of psychostimulant abuse and have been proposed as potential medications for the treatment of cocaine addiction. However, several (S)-2-carboalkoxy-substituted-3 alpha[bis(4-fluorophenyl)methoxy]tropane analogues were discovered to stimulate locomotor activity and substitute in subjects trained to discriminate cocaine, suggesting a role of the 2-position substituent in mediating these cocaine-like actions. Herein, we describe the synthesis of a series of novel N- and 2-substituted-3 alpha-[bis(4-fluoro-or 4-chlorophenyl)methoxy]tropane analogues. Most of these analogues demonstrated high affinity binding to the dopamine transporter (DAT; K-i = 1.8-40 nM), and selectivity over the other monoamine transporters and muscarinic M-1 receptors. When the (S)-2-carboalkoxy substituent was replaced with (S)-2-ethenyl, the resulting analogue 11 demonstrated the highest DAT binding affinity in the series (K-i = 1.81 nM) with DAT selectivity over serotonin transporters (SERT; 989-fold), norepinephrine transporters (NET; 261-fold) and muscarinic receptors (90-fold). When the 4'-F groups of compounds 5 (K-i = 2.94 nM) and 8 (K-i = 6.87 nM) were replaced with 4'-Cl in the (S)-2-carboalkoxy series, DAT binding affinities were slightly reduced (K-i = 12.6 and 14.6 nM for 6 and 7, respectively), yet inhibition of dopamine uptake potency remained comparably high (IC50 range = 1.5-2.5 nM). Interestingly, the 4'-Cl analogue (+/-)-6 substituted less in rats trained to discriminate cocaine than the 4'-F analogue (+/-)-5. These studies demonstrate that manipulation of the 2-, N-, and 3-position substituents in the 3 alpha-(diphenylmethoxy) tropane class of dopamine uptake inhibitors can result in ligands with high affinity and selectivity for the DAT, and distinctive in vivo pharmacological profiles that cannot be predicted by their effects in vitro.