Dextromethorphan/Quinidine in Migraine Prophylaxis: An Open-label Observational Clinical Study

Berkovich, Regina; Sokolov, Alexey Y.; Togasaki, Daniel M.; Yakupova, A. A.; Cesar, Paul-Henry; Sahai‐Srivastava, Soma

doi:10.1097/wnf.0000000000000272

Cited by 3 publications

(2 citation statements)

References 67 publications

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“…Dextromethorphan (Scheme A) has been one of the most widely used over-the-counter antitussives since its introduction in 1954. − When used at recommended antitussive doses, dextromethorphan shows no addictive properties or gastrointestinal side effects, making it superior to opioids . The combined use of dextromethorphan and quinidine has also recently been approved by the U.S. Food and Drug Administration and by the European Medicine Agency for the treatment of pseudobulbar affect. , With regard to synthesis, ( S )-1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline [( S )-1-(4-methoxybenzyl)-OHIQ, ( S )- 1a (Scheme B)] is the key synthetic intermediate in the industrial production of dextromethorphan .…”

Section: Introductionmentioning

confidence: 99%

Asymmetric Synthesis of a Key Dextromethorphan Intermediate and Its Analogues Enabled by a New Cyclohexylamine Oxidase: Enzyme Discovery, Reaction Development, and Mechanistic Insight

Huang

Wang

et al. 2020

J. Org. Chem.

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Metrics & MoreArticle Recommendations * sı Supporting Information ABSTRACT: (S)-1-(4-Methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline [(S)-1-(4-methoxybenzyl)-OHIQ, (S)-1a] is a key synthetic intermediate in the industrial production of dextromethorphan, one of the most widely used over-the-counter antitussives. We report here that a new cyclohexylamine oxidase discovered by genome mining, named CHAO CCH12-C2 , was able to completely deracemize 100 mM 1a under Turner's deracemization conditions to afford (S)-1a in 80% isolated yield and 99% ee at a semipreparative scale (0.4 mmol). When this biocatalytic reaction was scaled up to a gram scale (5.8 mmol), without reaction optimization (S)-1a was still isolated in 67% yield and 96% ee. The relatively higher k cat determined for CHAO CCH12-C2 was rationalized as one major factor rendering this enzyme capable of oxidizing 1a effectively at elevated substrate concentrations. Protein sequence alignment, analysis of our co-crystal structure of CHAO CCH12-C2 complexed with the product 1-(4-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline [1-(4-methoxybenzyl)-HHIQ, 2a], and the structure-guided mutagenesis study together indicated L295 is one of the critical residues for this efficient enzymatic oxidation process and supported the presence of two cavities as well as a catalytically important "aromatic cage" formed by F342, Y433, and FAD. The synthetic applicability of CHAO CCH12-C2 was further underscored by the stereoselective synthesis of various enantioenriched 1-benzyl-OHIQ derivatives of potential pharmaceutical importance at a semipreparative scale.

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Section: Introductionmentioning

confidence: 99%

Asymmetric Synthesis of a Key Dextromethorphan Intermediate and Its Analogues Enabled by a New Cyclohexylamine Oxidase: Enzyme Discovery, Reaction Development, and Mechanistic Insight

Huang

Wang

et al. 2020

J. Org. Chem.

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“…It is well-accepted that distinct enantiomers of chiral pharmaceutically active molecules may exhibit marked difference in pharmacokinetic, pharmacodynamics, and toxicological properties when interacted with bio-receptors. [1] For instance, dextromethorphan (Scheme 1a) is a widely used over-the-counter antitussive with superior safety properties, [2][3][4][5][6][7] whereas levomethorphan (Scheme 1b), the enantiomer of dextromethorphan, is a potent narcotic analgesic and strictly controlled substance worldwide. [7][8][9][10] Hence, it is critical to use dextromethorphan in its optically pure form.…”

Section: Introductionmentioning

confidence: 99%

Engineered Cyclohexylamine Oxidase with Improved Activity and Stereoselectivity for Asymmetric Synthesis of a Bulky Dextromethorphan Precursor and Its Analogues

Lin

et al. 2022

ChemCatChem

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Cyclohexylamine oxidase CHAO CCH12-C2 was previously discovered and utilized in the chemo-enzymatic synthesis of (S)-1-(4methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline ((S)-1 a), the key precursor for the industrial production of antitussive dextromethorphan. Herein, structure-guided semi-rational engineering and random mutagenesis were applied to CHAO CCH12-C2 , resulting in an evolved variant WXF-FM which possessed five point mutations: H68Q/E198G/L200V/I201L/V209S and displayed > 15-fold higher k cat and improved stereoselectivity towards (R)-1 a relative to the WT enzyme. WXF-FM-catalyzed deracemization of 200 mM of rac-1 a was achieved at gramscale under Turner's deracemization conditions, affording (S)-1 a in 76 % isolated yield with 97 % ee, demonstrating the effectiveness and great potential of this enzyme in the practical, green synthesis of dextromethorphan. Two bulky analogues of (S)-1 a were also afforded with much higher optical purities in WXF-FM-catalyzed reactions than those obtained in WT enzyme-catalyzed reactions. Through conducting complete deconvoluting experiments, presence of strong cooperative effect was revealed, and the mutational effect of H68Q on (R)-1 a was suggested to be possibly applicable to related cyclohexylamine oxidases. Molecular dynamics (MD) simulations indicated the enlargement of binding and entrance cavities, and the formation of a new hydrogen-bonding between FAD and (R)-1 a both likely contributed to the enhanced catalytic activity.

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Electrophysiological model of trigeminovascular nociception as a tool for experimental study of migraine pharmacotherapy

Dolgorukova¹,

Sokolov²

2021

Rus. Jour. of Pain

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Dextromethorphan/Quinidine in Migraine Prophylaxis: An Open-label Observational Clinical Study

Abstract: Our pilot study results provide evidence that DMQ shows promise as a candidate for larger clinical studies evaluating its efficacy for the prevention of migraine headaches.

Cited by 3 publications

References 67 publications

Asymmetric Synthesis of a Key Dextromethorphan Intermediate and Its Analogues Enabled by a New Cyclohexylamine Oxidase: Enzyme Discovery, Reaction Development, and Mechanistic Insight

Asymmetric Synthesis of a Key Dextromethorphan Intermediate and Its Analogues Enabled by a New Cyclohexylamine Oxidase: Enzyme Discovery, Reaction Development, and Mechanistic Insight

Engineered Cyclohexylamine Oxidase with Improved Activity and Stereoselectivity for Asymmetric Synthesis of a Bulky Dextromethorphan Precursor and Its Analogues

Electrophysiological model of trigeminovascular nociception as a tool for experimental study of migraine pharmacotherapy

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