Structural Remodeling of Cocaine: Design and Synthesis of Trisubstituted Cyclopropanes as Selective Serotonin Reuptake Inhibitors

Kozikowski, Alan P.; Zhao, Long; Zhang, Ao; Wang, Cheng Z.; Flippen‐Anderson, Judith L.; Johnson, Kenneth M.

doi:10.1002/cmdc.200500016

Cited by 10 publications

(9 citation statements)

References 40 publications

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“…Notwithstanding the fact that modafinil, cocaine, and amphetamines all interact with DAT, the pharmacology of modafinil is distinct from that of cocaine and amphetamines. Whereas cocaine (80) and amphetamines (49) bind to the DA transporter with nanomolar affinity, modafinil acts as a DAT ligand at micromolar concentrations (10, 14). This low affinity may contribute to the slow kinetics of its effect on extracellular DA concentration (discussed below).…”

Section: Why Do Modafinil and Other Commonly Used (And Abused) Dat Inmentioning

confidence: 99%

“…Considering the monoamine transporters DAT, NET, and SERT, modafinil is highly selective as a DAT ligand (10, 12, 13, 18), albeit at micromolar concentrations. Cocaine (80) and amphetamines (49) disrupt the function of all three of the cell-membrane monoamine transporters. Additionally, both cocaine and amphetamines disrupt the vesicular monoamine transporter that packages monoamines into vesicles within the cell (81).…”

Section: Why Do Modafinil and Other Commonly Used (And Abused) Dat Inmentioning

confidence: 99%

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Modafinil as a Catecholaminergic Agent: Empirical Evidence and Unanswered Questions

Wisor¹

2013

Front. Neurol.

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Modafinil, in its two clinical formulations (Provigil® and Nuvigil®), is a widely prescribed wake-promoting therapeutic agent. It binds competitively to the cell-membrane dopamine (DA) transporter and is dependent on catecholaminergic (dopaminergic and adrenergic) signaling for its wake-promoting effects. The clinical spectrum of effects for modafinil is distinct from the effects seen with other catecholaminergic agents. Relative to other commonly used agents that act through catecholaminergic mechanisms, modafinil has a relatively low abuse potential, produces wakefulness with an attenuated compensatory sleep recovery thereafter, and does not ameliorate cataplexy in narcolepsy. These clinically relevant phenomenological differences between modafinil and agents such as amphetamines and cocaine do not eliminate catecholaminergic effects as a possible mediator of its wake-promoting action; they merely reflect its unique pharmacological profile. Modafinil is an exceptionally weak, but apparently very selective, DA transporter inhibitor. The pharmacodynamic response to modafinil, as measured by DA levels in brain microdialyzate, is protracted relative to other agents that act via catecholaminergic mechanisms. The conformational constraints on the interaction of modafinil with the DA transporter – and probably, as a consequence, its effects on trace amine receptor signaling in the catecholaminergic cell – are unique among catecholaminergic agents. These unique pharmacological properties of modafinil should be considered both in seeking to thoroughly understand its putatively elusive mechanism of action and in the design of novel therapeutic agents.

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Section: Why Do Modafinil and Other Commonly Used (And Abused) Dat Inmentioning

confidence: 99%

Section: Why Do Modafinil and Other Commonly Used (And Abused) Dat Inmentioning

confidence: 99%

Modafinil as a Catecholaminergic Agent: Empirical Evidence and Unanswered Questions

Wisor¹

2013

Front. Neurol.

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“…Alternatively, treatment of 8 b with LiAlH 4 afforded the corresponding amino alcohol 11 . These compounds have been shown to be selective serotonin reuptake inhibitors 20…”

Section: Methodsmentioning

confidence: 99%

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2008

Environ. Prog.

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Hoch stereoselektiv: Die vorgestellte hoch enantio‐ und diastereoselektive Rhodium(II)‐katalysierte Cyclopropanierung von Alkenen mit einem Diazoreagens, das zwei Carboxygruppen trägt, nutzt die starke trans‐dirigierende Wirkung von Amiden, um die Enantioselektivität zu verbessern. Mono‐ und disubstituierte Olefine werden in guten Ausbeuten cyclopropaniert. nttl=N‐1,8‐Naphthoyl‐tert‐leucin.

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“…[20] Chemoselective reduction of the amide in the presence of the ester [21] could be carried out using borane-THF complexes, giving the b-aminocarboxy ester 12 containing a cyclopropane ring. Furthermore, 8 b is sufficiently electrophilic to give the corresponding linear chain 10 upon reaction with BuCuLiCN.…”

mentioning

confidence: 99%

“…These compounds have been shown to be selective serotonin reuptake inhibitors. [20] Chemoselective reduction of the amide in the presence of the ester [21] could be carried out using borane-THF complexes, giving the b-aminocarboxy ester 12 containing a cyclopropane ring. [2b] In summary, a highly enantio-and diastereoselective synthesis of cyclopropane 1,1-dicarboxylic derivatives has been developed.…”

mentioning

confidence: 99%

trans‐Directing Ability of Amide Groups in Cyclopropanation: Application to the Asymmetric Cyclopropanation of Alkenes with Diazo Reagents Bearing Two Carboxy Groups

Marcoux

Charette

2008

Angew Chem Int Ed

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Highly stereoselective: A highly enantioselective (up to 97 % ee) and diastereoselective (>30:1 d.r.) RhII‐catalyzed cyclopropanation of alkenes using a diazo reagent bearing two carboxy groups is described. This new methodology exploits the powerful trans‐directing ability of amides to improve enantiocontrol. Mono‐ and disubstituted olefins are cyclopropanated in good yields. nttl=N‐1,8‐naphthoyl‐tert‐leucine.

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Structural Remodeling of Cocaine: Design and Synthesis of Trisubstituted Cyclopropanes as Selective Serotonin Reuptake Inhibitors

Cited by 10 publications

References 40 publications

Modafinil as a Catecholaminergic Agent: Empirical Evidence and Unanswered Questions

Modafinil as a Catecholaminergic Agent: Empirical Evidence and Unanswered Questions

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trans‐Directing Ability of Amide Groups in Cyclopropanation: Application to the Asymmetric Cyclopropanation of Alkenes with Diazo Reagents Bearing Two Carboxy Groups

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