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Pharmaceutical Research

, Volume 12, Issue 10, pp 1430–1434 | Cite as

Conformational Analysis of Methylphenidate and Its Structural Relationship to Other Dopamine Reuptake Blockers Such as CFT

  • Mark Froimowitz
  • Kennerly S. Patrick
  • Vivian Cody
Article

Abstract

Purpose. 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.

Methods. A conformational analysis was performed with the MM2-87 program, a crystal of the (– )-threo HC1 salt was analyzed by x-ray crystallography, and the global minima of the (+ }-threo isomer and the potent dopamine reuptake blocker CFT were superimposed.

Results. 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.

Conclusions. 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.

methylphenidate molecular mechanics x-ray crystallography dopamine reuptake blockers absolute configuration pharmacophore 

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Copyright information

© Plenum Publishing Corporation 1995

Authors and Affiliations

  • Mark Froimowitz
    • 1
    • 2
  • Kennerly S. Patrick
    • 3
  • Vivian Cody
    • 4
  1. 1.Pharm-Eco LaboratoriesLexington
  2. 2.Alcohol and Drug Abuse Research Center, Harvard Medical SchoolMcLean HospitalBel-mont
  3. 3.Department of Pharmaceutical Sciences, College of PharmacyMedical University of South CarolinaCharleston
  4. 4.Hauptman-Woodward Medical Research Institute, Inc.

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