Absolute configurations of the enantiomeric pheniramines, methylphenidates, and pipradrols

Shafiee, Abbas; Marathe, Sudhir; Bhatkar, R.; Hite, G.

doi:10.1002/jps.2600561240

Cited by 7 publications

(2 citation statements)

References 10 publications

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“…First synthesized in 1944 and recognized as a stimulant in 1954, early chemical work is described primarily in the patent literature and was centered on the separation and interconversion of the so called (a) isomer and the biologically more active (b) isomer. The absolute (2 R ,2‘ R ; threo ) stereochemistry of the most active enantiomer of methylphenidate ( 1a ) was proven by chemical techniques. , A series of alkyl esters of (±)- threo -ritalinic acid was made in 1961 and shown to be less potent stimulants than 1a . In 1974 Faraj et al .…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Pharmacology of Potential Cocaine Antagonists. 2. Structure−Activity Relationship Studies of Aromatic Ring-Substituted Methylphenidate Analogs

et al. 1996

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As part of a program to develop medications which can block the binding of cocaine to the dopamine transporter, yet spare dopamine uptake, a series of aromatic ring-substituted methylphenidate derivatives was synthesized and tested for inhibitory potency in [3H]WIN 35,428 binding and [3H]dopamine uptake assays using rat striatal tissue. Synthesis was accomplished by alkylation of 2-bromopyridine with anions derived from various substituted phenylacetonitriles. In most cases, erythro compounds were markedly less potent than the corresponding (+/-)-threo-methylphenidate (TMP; Ritalin) derivatives. The ortho-substituted compounds were much less potent than the corresponding meta- and/or para-substituted derivatives. The most potent compound against [3H]WIN 35,428 binding, m-bromo-TMP, was 20-fold more potent than the parent compound, whereas the most potent compound against [3H]dopamine uptake, m,p-dichloro-TMP, was 32-fold more potent. Threo derivatives with m- or p-halo substituents were more potent than TMP, while electron-donating substituents caused little change or small loss of potency. All of the derivatives had Hill coefficients approaching unity, except m,p-dichloro-TMP, which had an nH of 2.0. Although the potency of the (+/-)-methylphenidate derivatives in the two assays was highly correlated (R2 = 0.986), the compounds m-chloro-,m-methyl-, and p-iodo-TMP were 4-5-fold more potent at inhibiting [3H]-WIN 35,428 binding than [3H]dopamine uptake (cocaine has a ratio of 2.3). These and other compounds may be promising candidates for further testing as potential partial agonists or antagonists of cocaine.

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Section: Introductionmentioning

confidence: 99%

Synthesis and Pharmacology of Potential Cocaine Antagonists. 2. Structure−Activity Relationship Studies of Aromatic Ring-Substituted Methylphenidate Analogs

et al. 1996

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“…[7][8][9][10] Subsequent studies focused on the separation of the two diastereomers and interconversion of (±)-erythro racemate to its (±)-threo counterpart. The (±)-threo racemate exists as two enantiomers, (+)-threo-MPH (2R,2'R) and (-)-threo-MPH (2S,2'S), and the absolute stereochemistry of the most pharmacologically active enantiomer of MPH ((+)-threo) has been characterized [11][12][13] and developed as a medication to treat ADHD in its own right. [14] There have also been efforts to prepare enantiomerically pure (2R,2'R)-(+)-threo-MPH.…”

Section: Introductionmentioning

confidence: 99%

Analytical characterization and pharmacological evaluation of the new psychoactive substance 4‐fluoromethylphenidate (4F‐MPH) and differentiation between the (±)‐threo and (±)‐erythro diastereomers

McLaughlin

Morris

Kavanagh

et al. 2017

Drug Testing and Analysis

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Misuse of (±)-threo-methylphenidate (methyl-2-phenyl-2-(piperidin-2-yl)acetate; Ritalin®, MPH) has long been acknowledged, but the appearance of MPH analogs in the form of ‘research chemicals’ has only emerged in more recent years. 4-Fluoromethylphenidate (4F-MPH) is one of these recent examples and this study presents the identification and analytical characterization of two powdered 4F-MPH products that were obtained from an online vendor in 2015. Interestingly, the products appeared to have originated from two distinct batches given that one product consisted of (±)-threo-4F-MPH isomers whereas the second sample consisted of a mixture of (±)-threo and (±)-erythro 4F-MPH. Monoamine transporter studies using rat brain synaptosomes revealed that the biological activity of the 4F-MPH mixture resided with the (±)-threo- and not the (±)-erythro isomers based on higher potencies determined for blockage of dopamine uptake (IC50 4F-MPHmixture = 66 nM vs. IC50 (±)-threo = 61 nM vs. IC50 (±)-erythro = 8,528 nM) and norepinephrine uptake (IC50 4F-MPHmixture = 45 nM vs. (±)-threo = 31 nM vs. IC50 (±)-erythro = 3,779 nM). In comparison, MPH was three times less potent than (±)-threo-4F-MPH at the dopamine transporter (IC50 = 131 nM) and around 2.5-times less potent at the norepinephrine transporter (IC50 = 83 nM). Both substances were catecholamine selective with IC50 values of 8,805 nM and >10,000 nM for (±)-threo-4F-MPH and MPH at the serotonin transporter. These findings suggest that the psychostimulant properties of (±)-threo-4F-MPH might be more potent in humans than MPH.

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Amphetamines: Structure-Activity Relationships

Biel¹,

Bopp

1978

Stimulants

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Absolute configurations of the enantiomeric pheniramines, methylphenidates, and pipradrols

Cited by 7 publications

References 10 publications

Synthesis and Pharmacology of Potential Cocaine Antagonists. 2. Structure−Activity Relationship Studies of Aromatic Ring-Substituted Methylphenidate Analogs

Synthesis and Pharmacology of Potential Cocaine Antagonists. 2. Structure−Activity Relationship Studies of Aromatic Ring-Substituted Methylphenidate Analogs

Analytical characterization and pharmacological evaluation of the new psychoactive substance 4‐fluoromethylphenidate (4F‐MPH) and differentiation between the (±)‐threo and (±)‐erythro diastereomers

Amphetamines: Structure-Activity Relationships

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