Kozikowski A P, Araldi G L, Prakash K R, Zhang M, Johnson K M
Drug Discovery Program, Institute of Cognitive and Computational Sciences, Georgetown University Medical Center, 3970 Reservoir Road, N.W., Washington, D.C. 20007-2197.
J Med Chem. 1998 Dec 3;41(25):4973-82. doi: 10.1021/jm9802564.
In our efforts to identify molecules that might act as cocaine antagonists or cocaine partial agonists, we have been involved in efforts to further elucidate the nature of cocaine's binding to the dopamine transporter (DAT) through strategic modifications of its structure. In the case of the substituent located at the 2-position of the tropane ring, studies have revealed the ability of the transporter to accommodate groups of diverse structure, including ester, ketone, alkyl, alkenyl, heterocyclic, and aryl substituents, without loss of DAT binding affinity. In the present study, we report our results pertaining to the ability of the DAT to accommodate the WIN-type structures possessing alkyl or aryl groups at the 2-position and which adopt either a chair or a boat conformation of the tropane ring. Moreover, we discuss the influence of the stereochemistry of these compounds in their selectivity for the DAT versus the serotonin transporter (5HTT). Additionally, we point out the importance of using Ki values rather than IC50 values when making such comparisons of transporter selectivity. One of the most interesting compounds identified in the present work is a 2, 3-diaryltropane 22 in a boat conformation that is highly selective (69-fold) for the DAT over the 5HTT. The ability to prepare this compound as well as related structures by our oxidopyridinium betaine-based dipolar cycloaddition strategy further underscores the versatility of this particular chemical approach to the preparation of diverse tropane analogues. The use of the optically pure olefin p-tolyl vinyl sulfoxide as the dipolarophile in this reaction allows access to these novel tropanes in nonracemic form.
在我们致力于鉴定可能作为可卡因拮抗剂或可卡因部分激动剂的分子的过程中，我们通过对可卡因结构进行策略性修饰，进一步阐明了可卡因与多巴胺转运体（DAT）结合的本质。就位于托烷环2位的取代基而言，研究表明转运体能够容纳多种结构的基团，包括酯基、酮基、烷基、烯基、杂环基和芳基取代基，而不会丧失对DAT的结合亲和力。在本研究中，我们报告了关于DAT容纳在2位具有烷基或芳基基团且托烷环呈椅式或船式构象的WIN型结构的能力的研究结果。此外，我们讨论了这些化合物的立体化学对其对DAT与5-羟色胺转运体（5HTT）选择性的影响。另外，我们指出在进行转运体选择性比较时使用Ki值而非IC50值的重要性。在本研究中鉴定出的最有趣的化合物之一是呈船式构象的2,3-二芳基托烷22，它对DAT的选择性比对5HTT高69倍。通过我们基于氧化吡啶鎓甜菜碱的偶极环加成策略制备该化合物以及相关结构的能力，进一步强调了这种特定化学方法在制备多种托烷类似物方面的通用性。在该反应中使用光学纯的烯烃对甲苯基乙烯亚砜作为亲偶极体，能够以非外消旋形式获得这些新型托烷。
