Investigations into the correlations between monoamine oxidase inhibition and other effects due to methylphenydate and its stereoisomers

Szporny, L; Görög, P.

doi:10.1016/0006-2952(61)90100-9

Cited by 51 publications

(25 citation statements)

References 5 publications

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“…It can exist as four possible stereoisomers, but is administered to patients as a racemic mixture of threo diastereomers (Ritalin). This is because the erythro isomers have been demonstrated to show very little central stimulant effect, whereas both racemates exhibit comparable acute hypertensive effects, monoamine oxidase inhibition and toxicity (Szporny and Gorog, 1961). Both in vitro and in vivo evaluation in the rat of the individual enantiomers of DL-threo-methylphenidate, have shown that the pharmacological activity resides predominantly in the D-threo enantiomer with the activity of the D-isomer being greater than that of the L-isomer in the induction of locomotor acitivity and the inhibition of tritiated dopamine and L-noradrenaline uptake into striatal and hypothalamic synaptosomes, respectively .…”

Section: Pharmacokineticsmentioning

confidence: 95%

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Methylphenidate: a review of its neuropharmacological, neuropsychological and adverse clinical effects

Leonard¹,

McCartan²,

White³

et al. 2004

Human Psychopharmacology

210

145

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Section: Pharmacokineticsmentioning

confidence: 95%

“…Despite the lack of evidence to suggest that methylphenidate enhances serotonergic function, there is in vitro evidence to show that high doses inhibit monoamine oxidase activity (Szporny and Gorog, 1961).…”

Section: Effect Of Methylphenidate On Monoamine Reuptakementioning

confidence: 99%

Methylphenidate: a review of its neuropharmacological, neuropsychological and adverse clinical effects

Leonard¹,

McCartan²,

White³

et al. 2004

Human Psychopharmacology

210

145

View full text Add to dashboard Cite

“…Results from pharmacological studies have shown that MAOA inhibitors were modestly effective in the clinical treatment of ADHD [Zametkin et al, 1985;Biederman and Steingard, 1991]. Methylphenidate, which is a first-line treatment for ADHD, not only inhibits the dopamine transporter but also MAOA [Solanto, 1998], however at rather high does [Szporny and Gorog, 1961]. Animal and human studies have yielded some encouraging evidence that MAOA may be associated with aggression and impulsivity, both of which are common traits in ADHD patients.…”

Section: Introductionmentioning

confidence: 96%

Association analyses of MAOA in Chinese Han subjects with attention‐deficit/hyperactivity disorder: Family‐based association test, case–control study, and quantitative traits of impulsivity

Liu

Guan

Chen

et al. 2011

American J of Med Genetics Pt B

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Monoamine oxidase A (MAOA) plays a critical role in the metabolism of monoamine neurotransmitters including serotonin (5-HT), norepinephrine (NE), and dopamine (DA). Genetic studies have found an association between MAOA and attention-deficit/hyperactivity disorder (ADHD), especially impulsivity. However, there has been inconsistency among studies which may be due to the complexity and heterogeneity of ADHD, including its sexual dimorphism and the presence of several subtypes. We conducted transmission disequilibrium tests (TDTs) in 1,253 trios and found no association between five single nucleotide polymorphisms (SNPs) of MAOA with ADHD in general or in the predominantly inattentive (ADHD-I) or combined types (ADHD-C), but with the predominantly hyperactive/impulsivity type (ADHD-HI). The association with MAOA was restricted to males, especially males with ADHD-HI. Logistic regression analyses of data from 1,824 cases and 957 controls did not indicate any association. We used analysis of covariance to analyze the association between MAOA genotype with the "inhibit" factor of the Behavior Rating Inventory of Executive Function (BRIEF) in 640 probands and performance on the Stroop test in 810 probands. Probands homozygous for risk alleles found in the TDT test had higher "inhibit" scores on the BRIEF scale which represents more severe impulsivity; this results also was restricted to males. No association was found with Stroop test performance. In conclusion, our results provide some evidence that MAOA may be associated with the ADHD-HI subtype and support the association between MAOA and impulsivity, which may be a potential endophenotype of ADHD. However, the results were strongly influenced by gender.

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“…In this way, a set of available tertiary amines as bases was investigated. In all cases a variable ratio of compounds 2 and 5 was observed ( Table 1, entries [8][9][10][11][12][13][14] and the use of KOt-Bu furnished the compound 5 as a major product (entry 15). Interestingly, the best yield of compound 2 (60%) was achieved when DBU was employed in the absence of a thiophile (Table 1, entry 14) in which thiazolidinone 5 was not isolated.…”

Section: Thementioning

confidence: 99%

“…Although the erythro-methylphenidate exhibits very few therapeutic properties and toxic hypertensive effects, 14 the stereoselective synthesis of the erythro-isomer can be helpful due to the possibility of resolution and epimerization of the erythro-isomer. 2,15 This approach was used early in the original synthesis of (+/−)-threomethylphenidate.…”

Section: Thementioning

confidence: 99%

A concise and stereoselective synthesis of (+/−)-erythro-methylphenidate

Russowsky

Neto

2003

Tetrahedron Letters

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Abstract-A concise and stereoselective synthesis of racemic erythro-methylphenidate (1) is described. The coupling reaction between piperidine-2-thione (3) and 2-bromo-2-phenylmethylacetate (4) afforded the b-enaminocarbonyl compound 2 in 60% yield by a modified Eschenmoser sulfide contraction reaction. In most cases the bicyclic thiazolidinone 5 was produced. Diastereoselective reduction of 2 in the presence of borohydrydes furnished the (+/−)-erythro-methylphenidate in good yields with dr >95%. © 2003 Elsevier Science Ltd. All rights reserved. The(+/−)-threo-methylphenidate hydrochloride (Ritalin ® ), is an indirect catecholamine agonist, 1 and is the drug treatment of choice for the attention deficit/ hyperactivity disorder (AD/HD), 2 one of the most common behavioral disorders of childhood which affects 5-10% of the general population. 3 The activity of Ritalin ® promotes an enhancement of the cognitive performance in both adults and children diagnosed with AD/HD. 4 Although Ritalin ® is available in the market as the racemate, the (2R,2%R)-(+)-threo-methylphenidate has been reported to be up to 38 times 5 more active than (2S,2%S)-(−)-threo-methylphenidate and several racemic 6-9 and chiral 10-13 synthesis of threo-methylphenidate were reported previously.Although the erythro-methylphenidate exhibits very few therapeutic properties and toxic hypertensive effects, 14 the stereoselective synthesis of the erythro-isomer can be helpful due to the possibility of resolution and epimerization of the erythro-isomer. 2,15 This approach was used early in the original synthesis of (+/−)-threomethylphenidate. Close to this, an enantioselective synthesis of (2S,2%S)-erythro-methylphenidate was recently published by Due to this fact and relating to our interest in the synthesis of b-aminocarbonyl compounds 17,18 we would like to communicate in this paper our approach to the synthesis of (+/−)-erythro-methylphenidate 1 applying a new concise stereoselective synthetic strategy.We envisaged obtaining 1 based on a stereoselective reduction of a b-enaminocarbonyl compound 2 which is readily accessible by the Eschenmoser sulfide contraction reaction 19,20 (Scheme 1).The needed piperidine-2-thione (3) was prepared in 91% yield after reaction of piperidine-2-one with Lawesson reagent. 21 The bromoester 4 was obtained by sterification and subsequent a-bromination 22 of 2-phenylacetic acid in 71% overall yield after purufication by horizontal destilation at reduced pressure. Next, the condensation reaction of compounds 3 and 4 was carried out under the Eschenmoser sulfide contraction reaction Scheme 1. The retrosynthetic analysis of 1 based on the eschemoser sulfide contraction reaction.

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Investigations into the correlations between monoamine oxidase inhibition and other effects due to methylphenydate and its stereoisomers

Cited by 51 publications

References 5 publications

Methylphenidate: a review of its neuropharmacological, neuropsychological and adverse clinical effects

Methylphenidate: a review of its neuropharmacological, neuropsychological and adverse clinical effects

Association analyses of MAOA in Chinese Han subjects with attention‐deficit/hyperactivity disorder: Family‐based association test, case–control study, and quantitative traits of impulsivity

A concise and stereoselective synthesis of (+/−)-erythro-methylphenidate

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