Froimowitz M, Patrick K S, Cody V
Pharm-Eco Laboratories, Lexington, Massachusetts 02173, USA.
Pharm Res. 1995 Oct;12(10):1430-4. doi: 10.1023/a:1016262815984.
This work was performed 1) to determine the conformational preferences of the threo and erythro isomers of the dopamine reuptake blocker methylphenidate, 2) to determine the crystal conformation of the threo isomer, 3) to confirm the absolute configuration of the more active threo enantiomer, and 4) to incorporate the compound into a previously determined pharmacophore for dopamine reuptake blockers.
A conformational analysis was performed with the MM2-87 program, a crystal of the (-)-threo HCl salt was analyzed by x-ray crystallography, and the global minima of the (+)-threo isomer and the potent dopamine reuptake blocker CFT were superimposed.
In the global minimum of the threo isomer, the carbonyl oxygen of the ester group is oriented toward the ammonium group as was also found in the crystal state. In the erythro isomer, the ester group prefers an extended conformation relative to the piperidine group. The absolute configuration of the biologically active (+)-threo enantiomer was confirmed to be R,R. The atomic sequence from the amine group through the ester group is identical in the active enantiomers of methylphenidate and CFT.
The dopamine reuptake protein requires a precise orientation of the ammonium and ester groups but allows considerable leeway in the position of the phenyl ring. The pKa of the threo isomer is predicted to be higher than that of the erythro isomer.
开展本研究工作是为了1）确定多巴胺再摄取阻滞剂哌醋甲酯的苏式和赤式异构体的构象偏好；2）确定苏式异构体的晶体构象；3）确认活性更强的苏式对映体的绝对构型；4）将该化合物纳入先前确定的多巴胺再摄取阻滞剂药效团中。
使用MM2 - 87程序进行构象分析，通过X射线晶体学分析（-）-苏式盐酸盐的晶体，并将（+）-苏式异构体和强效多巴胺再摄取阻滞剂CFT的全局最小值进行叠加。
在苏式异构体的全局最小值中，酯基的羰基氧朝向铵基，这在晶体状态下也有发现。在赤式异构体中，酯基相对于哌啶基更倾向于伸展构象。具有生物活性的（+）-苏式对映体的绝对构型被确认为R,R。哌醋甲酯和CFT的活性对映体中，从胺基到酯基的原子序列是相同的。
多巴胺再摄取蛋白需要铵基和酯基的精确取向，但对苯环的位置允许有相当大的自由度。预计苏式异构体的pKa高于赤式异构体。
