Synthesis and ligand binding studies of 4'-iodobenzoyl esters of tropanes and piperidines at the dopamine transporter.
Synthesis and ligand binding studies of 4'-iodobenzoyl esters of tropanes and piperidines at the dopamine transporter.
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托烷和哌啶的 4-碘苯甲酰酯在多巴胺转运蛋白上的合成和配体结合研究。
DOI：
10.1021/jm970121i
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发表时间：
1997
影响因子：
7.3
通讯作者：
Seale,TW
中科院分区：
文献类型：
--
作者：
Singh,S;Basmadjian,GP;Avor,KS;Pouw,B;Seale,TW
合成了四个可卡因类似物和两个可卡因同系物，被设计为有效的可卡因拮抗剂。淫羊藿甲酯(13)或适当取代的哌啶醇(19，21)与适当取代的4-碘苯甲酰氯反应生成4-碘苯甲酰基托烷和哌啶(5−8)。以2‘-乙酰氧基可卡因(12)为原料，与饱和的甲醇进行选择性酯交换反应，制得2’-羟基可卡因(9)。以乙酰水杨酰氯(23)和淫羊藿甲酯(13)为原料合成了2‘-乙酰氧基可卡因(12)。在[~3H]Win-35428的多巴胺转运体上测定了这些化合物的结合亲和力。可卡因4‘-位上的碘取代降低了多巴胺转运体的结合能力，而2’-位的羟基或乙酰氧基与可卡因相比显示出更高的多巴胺转运体结合能力(分别是可卡因的10倍和3.58倍)。2‘-羟基化还使4’-碘可卡因(5)的结合力提高了10倍。用哌啶取代托烷环会导致结合亲和力较差。
Four analogs and two homologs of cocaine, designed as potent cocaine antagonists, were synthesized. The SN2 reaction between ecgonine methyl ester (13) or appropriately substituted piperidinol (19,21) and appropriately substituted 4-iodobenzoyl chloride gave 4-iodobenzoyl esters of tropanes and piperidines (5−8). 2‘-Hydroxycocaine (9) was obtained from 2‘-acetoxycocaine (12) by selective transesterification with MeOH saturated with dry HCl gas. 2‘-Acetoxycocaine (12) was synthesized from acetylsalicyloyl chloride (23) and ecgonine methyl ester (13). The binding affinities of these compounds were determined at the dopamine transporter for the displacement of [3H]WIN-35428. An iodo group substitution at the 4‘-position of cocaine decreased dopamine transporter binding potency, while a hydroxy or acetoxy group at the 2‘-position exhibited increased binding potency for the dopamine transporter compared to cocaine (10- and 3.58-fold, respectively). 2‘-Hydroxylation also enhanced the binding potency of 4‘-iodococaine (5) by 10-fold. Replacement of the tropane ring with piperidine led to poor binding affinities.