Chen Z, Izenwasser S, Katz J L, Zhu N, Klein C L, Trudell M L
Department of Chemistry, University of New Orleans, Louisiana 70148, USA.
J Med Chem. 1996 Nov 22;39(24):4744-9. doi: 10.1021/jm960507d.
A series of 9-methyl-3 beta-phenyl-2-substituted-9-azabicyclo[3.3.1]nonane derivatives were synthesized and evaluated as cocaine-binding site ligands at the dopamine transporter (DAT). The conformation of the bicyclic structures and the stereochemistry of the substituents were determined by NMR and X-ray crystallography. The in vitro binding affinity (Ki) of the 9-azabicyclo[3.3.1]nonane derivatives was measured in rat caudate-putamen tissue, and they were found to be 100-fold (Ki = 2-14 microM) less potent than cocaine and other tropane analogs. From these results it is evident that the cocaine-binding site at the DAT is very sensitive to structural modifications of the unsubstituted methylene bridge [C(6)-C(7)] of cocaine and cocaine-like compounds.
合成了一系列9-甲基-3β-苯基-2-取代-9-氮杂双环[3.3.1]壬烷衍生物，并将其作为多巴胺转运体（DAT）上可卡因结合位点配体进行评估。通过核磁共振（NMR）和X射线晶体学确定了双环结构的构象和取代基的立体化学。在大鼠尾状核-壳核组织中测量了9-氮杂双环[3.3.1]壬烷衍生物的体外结合亲和力（Ki），发现它们的效力比可卡因和其他托烷类似物低100倍（Ki = 2-14 microM）。从这些结果可以明显看出，DAT上的可卡因结合位点对可卡因和可卡因样化合物未取代的亚甲基桥[C(6)-C(7)]的结构修饰非常敏感。
