Quantitative structure–activity relationship studies of threo-methylphenidate analogs

Misra, Milind; Shi, Qing; Ye, Xiaocong; Gruszecka-Kowalik, Ewa; Bu, Wei; Liu, Zhanzhu; Schweri, Margaret M.; Deutsch, Howard M.; Venanzi, Carol A.

doi:10.1016/j.bmc.2010.08.034

Cited by 13 publications

(30 citation statements)

References 74 publications

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“…[14,15] Molecular structures and the respective activities at the DAT have been reported for many of these compounds in the scientific literature, thus making the targeted synthesis of potent phenidate analogs for the drug market likely. [16] Phenidates were also recently seized by…”

Section: Introductionmentioning

confidence: 99%

“…Little is known about the pharmacology and hazards of phenidate analogs despite their structural similarity. [11,12,[16][17][18] However, ethylphenidate (4) has been linked to a number of deaths [19][20][21][22][23] and concerns have been expressed about ethylphenidate injection in drug users. [21,22] It has also been long recognized that ethylphenidate is formed in vivo following co-administration of methylphenidate with alcohol.…”

Section: Introductionmentioning

confidence: 99%

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Analysis of six ‘neuro‐enhancing’ phenidate analogs

Klare¹,

Neudörfl

Brandt

et al. 2017

Drug Testing and Analysis

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Analysis of six ‘neuro‐enhancing’ phenidate analogs

Klare¹,

Neudörfl

Brandt

et al. 2017

Drug Testing and Analysis

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“…In particular, we focused on the well-known attention deficit hyperactivity disorder (ADHD) drug (±)- threo -methylphenidate ((±)- 1 ), analogs of which have received significant attention as potential cocaine abuse therapeutics. 17,18 Previous SAR studies 19 indicated the 3′ and 4′ positions of the aromatic ring within (±)- 1 could potentially be modified to include the 3′-I, 4′-N 3 motif without adversely affecting DAT binding affinity (vide infra). With this in mind, compound (±)- 6 was designed and envisioned as a compact DAT photoprobe bearing no linker functionality.…”

mentioning

confidence: 99%

“…However, replacing the aniline of compound (±)- 14 with a photoreactive azide group, resulting in target probe (±)- 6 , gave an ~2.3-fold increase in hDAT affinity. In particular, our design of target photoprobe (±)- 6 stemmed from known methylphenidate analog (±)- 17 , 19 which features hydrophobic chlorine atoms at positions 3′ and 4′ of the aromatic ring. Consistent with a previous report, 19 compound (±)- 17 displayed high DAT affinity in our hands ( K i = 1.8 ± 0.4 nM).…”

mentioning

confidence: 99%

“…In particular, our design of target photoprobe (±)- 6 stemmed from known methylphenidate analog (±)- 17 , 19 which features hydrophobic chlorine atoms at positions 3′ and 4′ of the aromatic ring. Consistent with a previous report, 19 compound (±)- 17 displayed high DAT affinity in our hands ( K i = 1.8 ± 0.4 nM). In turn, we hypothesized replacement of the hydrophobic chlorine atoms in (±)- 17 with hydrophobic iodine and azide groups would result a photoprobe with retained DAT affinity.…”

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confidence: 99%

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Evolution of a Compact Photoprobe for the Dopamine Transporter Based on (±)-threo-Methylphenidate

Lapinsky

Yarravarapu

Nolan

et al. 2012

ACS Med. Chem. Lett.

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The development of photoaffinity ligands for determining covalent points of attachment to the dopamine transporter (DAT) has predominantly focused on tropane-based compounds bearing variable-length linkers between the photoreactive group and inhibitor pharmacophore. In order to expand the array of photoprobes useful for mapping inhibitor-binding pockets within the DAT, a compact non-tropane ligand was synthesized featuring a photoreactive azide and iodine tag directly attached to the aromatic ring of (±)-threo-methylphenidate. (±)-threo-4-Azido-3-iodomethylphenidate ((±)-6); Ki = 4.0 ± 0.8 nM) displayed high affinity for hDAT. Moreover, a radioiodinated analog of (±)-6 demonstrated covalent ligation to the DAT in cultured cells and rat striatal membranes, thus suggesting the potential utility of this photoprobe in DAT structure-function studies.

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Designer drugs: mechanism of action and adverse effects

2020

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Psychoactive substances with chemical structures or pharmacological profiles that are similar to traditional drugs of abuse continue to emerge on the recreational drug market. Internet vendors may at least temporarily sell these so-called designer drugs without adhering to legal statutes or facing legal consequences. Overall, the mechanism of action and adverse effects of designer drugs are similar to traditional drugs of abuse. Stimulants, such as amphetamines and cathinones, primarily interact with monoamine transporters and mostly induce sympathomimetic adverse effects. Agonism at l-opioid receptors and c-aminobutyric acid-A (GABA A) or GABA B receptors mediates the pharmacological effects of sedatives, which may induce cardiorespiratory depression. Dissociative designer drugs primarily act as N-methyl-D-aspartate receptor antagonists and pose similar health risks as the medically approved dissociative anesthetic ketamine. The cannabinoid type 1 (CB 1) receptor is thought to drive the psychoactive effects of synthetic cannabinoids, which are associated with a less desirable effect profile and more severe adverse effects compared with cannabis. Serotonergic 5-hydroxytryptamine-2A (5-HT 2A) receptors mediate alterations of perception and cognition that are induced by serotonergic psychedelics. Because of their novelty, designer drugs may remain undetected by routine drug screening, thus hampering evaluations of adverse effects. Intoxication reports suggest that several designer drugs are used concurrently, posing a high risk for severe adverse effects and even death.

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Quantitative structure–activity relationship studies of threo-methylphenidate analogs

Cited by 13 publications

References 74 publications

Analysis of six ‘neuro‐enhancing’ phenidate analogs

Analysis of six ‘neuro‐enhancing’ phenidate analogs

Evolution of a Compact Photoprobe for the Dopamine Transporter Based on (±)-threo-Methylphenidate

Designer drugs: mechanism of action and adverse effects

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