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

  title={Conformational Analysis of Methylphenidate and Its Structural Relationship to Other Dopamine Reuptake Blockers Such as CFT},
  author={Mark Froimowitz and Kennerly Sexton Patrick and Vivian Cody},
  journal={Pharmaceutical Research},
AbstractPurpose. 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… 

Quantitative structure-activity relationship studies of threo-methylphenidate analogs.

Conformational analysis of methylphenidate: comparison of molecular orbital and molecular mechanics methods

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Conformational Analysis and a Crystal Structure of Bupropion, an Antidepressant with Dopamine Reuptake Blocking Activity

The three-dimensional structure of the preferred conformer of bupropion is consistent with the three- dimensional structures of other dopamine reuptake blockers such as cocaine, CFT, and methylphenidate.

Singular value decomposition of torsional angles of analogs of the dopamine reuptake inhibitor GBR 12909

Singular Value Decomposition (SVD) was used to group conformations of GBR 12909 analogs by the similarity of their nonring torsional angles, resulting in the development of a novel scaling technique for circular data and in the grouping of molecular conformations using a technique that is independent of molecular alignment.

Solution- and solid-state conformations of C(α)-alkyl analogues of methylphenidate (Ritalin) salts: avoidance of gauche(+)gauche(-) interactions.

Alkyl analogues of methylphenidate (Ritalin) salts are slow onset, long duration dopamine reuptake inhibitors with a potential use as a cocaine abuse pharmacotherapy and the stereochemistry of the species observed via NMR seems to arise from specific combinations of N-methyl orientation and avoidance of sterically unfavorable gauche(-)gauche(+) arrangements.

Hierarchical clustering analysis of flexible GBR 12909 dialkyl piperazine and piperidine analogs

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Ethanol elevates methylphenidate plasma concentrations and yields the metabolite ethylphenidate, and binding selectivity for dopamine versus norepinephrine transporters was greater for (+)-2 than for cocaine.

Methylphenidate inhibits cytochrome P450 in the Swiss Webster mouse

Results indicate that MPH inhibits the CYP450 system following both abuse and therapeutic scenarios, however, this effect was dependent on both the isoform of CYP 450 and the duration of MPH administration.

Ethylphenidate as a selective dopaminergic agonist and methylphenidate-ethanol transesterification biomarker.

We review the pharmaceutical science of ethylphenidate (EPH) in the contexts of drug discovery, drug interactions, biomarker for dl-methylphenidate (MPH)-ethanol exposure, potentiation of dl-MPH



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The conformational properties and receptor affinities of these compounds were found to be entirely consistent with the ligand model, and the importance of the correct orientation of the ammonium hydrogen for high affinity at the D2 receptor is emphasized.

Pharmacology of the enantiomers of threo-methylphenidate.

Results suggest that synaptic inhibition of catecholaminergic uptake by d-threo-MPH may be involved fundamentally in behavioral and pressor effects of the racemic drug.

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Con conformational analyses have been performed on cocaine, the potent analog 2β‐carbomethoxy‐3β‐(4‐fluorophenyl)tropane (CFT, 2), and a group of dopamine reuptake blockers that contain two phenyl rings, finding the N‐methyl groups in 1 and 2 are found to strongly prefer the equatorial position of the piperidine ring.

Steric aspects of adrenergic drugs. XII. Some peripheral effects of (+-)-erythro- and (+-)-threo-methylphenidate.

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These agents have sufficient structural and conformational differences to permit a rationale to be developed which explains their differences in potency as inhibitors of the uptake of norepinephrine.

Synthesis and pharmacology of hydroxylated metabolites of methylphenidate.

Findings suggest that metabolite 5a may play a role in the pharmacology of 1a, and the intracerebroventricular administration of acids 2a, 2b, 6 a, and 6b all produced a small increase in locomotor activity relative to their methyl esters which was not appreciably affected by stereochemistry or para-hydroxylation.

Spin probes as mechanistic inhibitors and active site probes of thymidylate synthetase.

The set of probes used for the binding and inhibition of thymidylate synthetase and as topographical probes of its active site gives direct experimental evidence that an electron-withdrawing C-5 substituent primarily affects the formation of the ternary complex and will not substantially influence the stability of the binary complex.

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