Lomenzo S A, Izenwasser S, Katz J L, Terry P D, Zhu N, Klein C L, Trudell M L
Department of Chemistry, University of New Orleans, Louisiana 70148, USA.
J Med Chem. 1997 Dec 19;40(26):4406-14. doi: 10.1021/jm970549h.
A series of 6-alkyl-3 beta-benzyl-2-[(methoxycarbonyl)methyl]tropane analogues were synthesized and evaluated as cocaine binding site ligands at the dopamine transporter (DAT). The in vitro affinity (Ki) for the DAT of the 6-alkyl-3 beta-benzyl-2-[(methoxycarbonyl) methyl]tropane analogues was determined by inhibition of [3H]WIN 35,428 in rat caudate putamen tissue. The inhibition of dopamine uptake (IC50) was also measured for selected compounds which demonstrated moderate affinity for the dopamine transporter. The unsubstituted enantiopure analogues (-)-19a (Ki = 33 nM) and surprisingly (+)-20a (Ki = 60 nM) were found to be almost equipotent with the high-affinity binding components of cocaine and WIN 35,065-2 and exhibited slightly more potent dopamine uptake inhibition than both cocaine and WIN 35,065-2. In general, substitution at the 6-position of racemic 19a and 20a with alkyl groups was found to result in decreased activity relative to increased chain length of the substituent. The 3 beta-benzyl-2 beta-[(methoxycarbonyl)methyl]-6 beta-methyltropane (21b; Ki = 57 nM) was the only 6-alkyl derivative to exhibit moderately potent activity. The 6 beta-isomer 21b was 4-fold more potent than the 6 alpha-isomer 19b (Ki = 211 nM) and was nearly equipotent with (-)-19a and (+)-20a as well as with cocaine and WIN 35,065-2. The results of this study further demonstrate the steric constraints associated with the C(6)-C(7) methylene bridge of the tropane ring system for molecular recognition of cocaine analogues at the cocaine binding site(s) on the DAT.
合成了一系列6-烷基-3β-苄基-2-[(甲氧基羰基)甲基]托烷类似物，并作为多巴胺转运体（DAT）上可卡因结合位点配体进行了评估。通过抑制大鼠尾状核壳核组织中的[3H]WIN 35,428来测定6-烷基-3β-苄基-2-[(甲氧基羰基)甲基]托烷类似物对DAT的体外亲和力（Ki）。还对选定的对多巴胺转运体具有中等亲和力的化合物测定了多巴胺摄取抑制率（IC50）。发现未取代的对映体纯类似物（-）-19a（Ki = 33 nM）以及令人惊讶的（+）-20a（Ki = 60 nM）与可卡因和WIN 35,065-2的高亲和力结合成分几乎等效，并且对多巴胺摄取的抑制作用比可卡因和WIN 35,065-2略强。一般而言, 外消旋体19a和20a的6位被烷基取代后，相对于取代基链长增加，活性降低。3β-苄基-2β-[(甲氧基羰基)甲基]-6β-甲基托烷（21b；Ki = 57 nM）是唯一具有中等活性的6-烷基衍生物。6β-异构体21b的活性比6α-异构体19b（Ki = 211 nM）高4倍，与（-）-19a、（+）-20a以及可卡因和WIN 35,065-2几乎等效。本研究结果进一步证明了托烷环系统中C(6)-C(7)亚甲基桥在DAT上可卡因结合位点对可卡因类似物进行分子识别时的空间限制。
