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

@article{Froimowitz2004ConformationalAO,
  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},
  year={2004},
  volume={12},
  pages={1430-1434}
}
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… Expand
Quantitative structure-activity relationship studies of threo-methylphenidate analogs.
TLDR
Complementary two-dimensional and three-dimensional Quantitative Structure-Activity Relationship (QSAR) techniques were used to derive a preliminary model for the dopamine transporter (DAT) binding affinity and the potential usefulness of the CoMFA models was demonstrated by the prediction of the binding affinity of methyl 2-(naphthalen-1-yl)-2-(piperidin-2-yl)acetate, an analog not in the original data set. Expand
Conformational analysis of methylphenidate: comparison of molecular orbital and molecular mechanics methods
TLDR
The random search (RS) conformational analysis technique using the Tripos force field was found to be capable of locating the minima found by the molecular orbital methods using systematic grid search, suggesting that the RS/Tripos forceField/vacuum phase protocol is a reasonable choice for locating the local minima of MP. Expand
Conformational Analysis and a Crystal Structure of Bupropion, an Antidepressant with Dopamine Reuptake Blocking Activity
TLDR
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. Expand
Singular value decomposition of torsional angles of analogs of the dopamine reuptake inhibitor GBR 12909
TLDR
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. Expand
Solution- and solid-state conformations of C(α)-alkyl analogues of methylphenidate (Ritalin) salts: avoidance of gauche(+)gauche(-) interactions.
TLDR
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. Expand
Vinylogous amide analogs of methylphenidate.
TLDR
In an effort to produce compounds with longer durations of action, ketone analogs of methylphenidate are synthesized which, however, appear to be highly unstable due to a highly acidic proton alpha to the ketone and phenyl groups. Expand
Hierarchical clustering analysis of flexible GBR 12909 dialkyl piperazine and piperidine analogs
TLDR
This study illustrates the utility of using hierarchical clustering for the classification of conformers of highly flexible molecules in terms of the three-dimensional spatial orientation of key pharmacophore elements. Expand
Synthesis and pharmacology of ethylphenidate enantiomers: the human transesterification metabolite of methylphenidate and ethanol.
TLDR
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. Expand
Methylphenidate inhibits cytochrome P450 in the Swiss Webster mouse
TLDR
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. Expand
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-MPHExpand
...
1
2
3
4
...

References

SHOWING 1-10 OF 21 REFERENCES
Biologically active conformers of phenothiazines and thioxanthenes. Further evidence for a ligand model of dopamine D2 receptor antagonists.
TLDR
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. Expand
Pharmacology of the enantiomers of threo-methylphenidate.
TLDR
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. Expand
Conformational analysis of cocaine, the potent analog 2β‐carbomethoxy‐3β‐(4‐fluorophenyl)tropane (CFT), and other dopamine reuptake blockers
TLDR
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. Expand
Steric aspects of adrenergic drugs. XII. Some peripheral effects of (+-)-erythro- and (+-)-threo-methylphenidate.
The ability of the diastereoisomers of methylphenidate to enhance responses to norepinephrine correlates with their known abilities to produce central nervous system stimulation. On the basis of aExpand
Conformational similarities between molecular models of phenethylamine and of potent inhibitors of the uptake of tritiated norepinephrine by adrenergic nerves in rabbit aorta.
TLDR
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. Expand
Synthesis and pharmacology of hydroxylated metabolites of methylphenidate.
TLDR
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. Expand
Substituted 3-phenyltropane analogs of cocaine: synthesis, inhibition of binding at cocaine recognition sites, and positron emission tomography imaging.
TLDR
The feasibility of synthesizing high-affinity ligands for cocaine recognition sites and their suitability as PET imaging ligand for cocaine receptors in vivo is demonstrated. Expand
Spin probes as mechanistic inhibitors and active site probes of thymidylate synthetase.
TLDR
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. Expand
[3H]Threo‐(±)‐Methylphenidate Binding to 3,4‐Dihydroxyphenylethylamine Uptake Sites in Corpus Striatum: Correlation with the Stimulant Properties of Ritalinic Acid Esters
TLDR
The observations suggest that the binding sites for [3H]threo‐(±)‐methyl‐phenidate described here are associated with a dopamine uptake or transport complex, and that these sites may mediate the motor stimulant properties of ritalinic acid esters such as methylphenidate. Expand
Investigations into the correlations between monoamine oxidase inhibition and other effects due to methylphenydate and its stereoisomers
Abstract The inhibitory activity of methylphenydate and of threo- and erythromethylphenydate in homogenates from liver, brain and kidney were investigated. This inhibition was also demonstrated inExpand
...
1
2
3
...