N-Substituted Epoxymorphinans

Clark, Robert L.; Pessolano, A. A.; Weijlard, John; Pfister, Kai F.

doi:10.1021/ja01116a024

Cited by 38 publications

(17 citation statements)

References 5 publications

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“…A significant illustration of the importance of N-demethylation is its application to opiate alkaloids. Replacement of the N-methyl group in opiates with short alkyl chains (typically of 3-5 carbons) such as the cyclopropylmethyl and allyl groups has been shown to exhibit strong antagonist activity [4][5][6][7][8][9]. Synthetic, pharmaceutical opiates of this kind include naloxone (12, Figure 3), which is administered in the event of a heroin overdose to overcome the potentially fatal effects of respiratory depression.…”

Section: The Importance Of N-demethylationmentioning

confidence: 99%

N-Demethylation of Alkaloids

Thavaneswaran

McCamley

Scammells

2006

Natural Product Communications

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The removal of an N-methyl group, or N-demethylation, is a useful chemical transformation in organic synthesis which has particular importance in the field of alkaloid chemistry. Historically, tertiary N-methyl alkaloids have been N-demethylated using the same methods as for N-dealkylating tertiary amines. Such methodologies have included the von Braun reaction, the use of chloroformate and azodicarboxylate reagents and the Polonovski reaction, amongst others. Photochemical and biochemical procedures have also been successfully employed. This review will examine these N-demethylation procedures, with special emphasis on their application to opiate alkaloids.

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Section: The Importance Of N-demethylationmentioning

confidence: 99%

N-Demethylation of Alkaloids

Thavaneswaran

McCamley

Scammells

2006

Natural Product Communications

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“…Altogether 36 compounds have been synthetized and most of them are new molecules, only N -carboxymethyl-normorphine ethyl ester, and N -carboxyethyl-norcodeine ethyl ester were previously synthesized [ 42 , 43 ]. The synthesis of nor-compounds (normorphine, dihydronormorphine, norcodeine, dihydronorcodeine, noroxymorphone and noroxycodone) by N -demethylation with α-chloroethyl chloroformate was accomplished.…”

Section: Methodsmentioning

confidence: 99%

Synthesis of Potential Haptens with Morphine Skeleton and Determination of Protonation Constants

et al. 2020

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Vaccination could be a promising alternative warfare against drug addiction and abuse. For this purpose, so-called haptens can be used. These molecules alone do not induce the activation of the immune system, this occurs only when they are attached to an immunogenic carrier protein. Hence obtaining a free amino or carboxylic group during the structural transformation is an important part of the synthesis. Namely, these groups can be used to form the requisite peptide bond between the hapten and the carrier protein. Focusing on this basic principle, six nor-morphine compounds were treated with ethyl acrylate and ethyl bromoacetate, while the prepared esters were hydrolyzed to obtain the N-carboxymethyl- and N-carboxyethyl-normorphine derivatives which are considered as potential haptens. The next step was the coupling phase with glycine ethyl ester, but the reactions did not work or the work-up process was not accomplishable. As an alternative route, the normorphine-compounds were N-alkylated with N-(chloroacetyl)glycine ethyl ester. These products were hydrolyzed in alkaline media and after the work-up process all of the derivatives contained the free carboxylic group of the glycine side chain. The acid-base properties of these molecules are characterized in detail. In the N-carboxyalkyl derivatives, the basicity of the amino and phenolate site is within an order of magnitude. In the glycine derivatives the basicity of the amino group is significantly decreased compared to the parent compounds (i.e., morphine, oxymorphone) because of the electron withdrawing amide group. The protonation state of the carboxylate group significantly influences the basicity of the amino group. All of the glycine ester and the glycine carboxylic acid derivatives are currently under biological tests.

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“…The synthesis of N -phenethylnormorphine ( 1 ) was performed from normorphine by alkylation with 2-phenylethyl bromide according to Clark et al [26] using N,N -dimethylformamide (DMF) instead of ethanol as solvent, which provided higher yields. Similarly, N -phenylpropylnormorphine ( 2 ) was synthesized from normorphine using 3-phenylpropyl bromide as alkylating agent.…”

Section: Methodsmentioning

confidence: 99%

“…SAR studies were performed on a series comprising of four derivatives of morphine ( 1–4 ) and two derivatives of oxymorphone ( 5 and 6 ) ( Figure 1 ). Although the synthesis of compounds 1 [26] , [27] and 3 [18] has been reported about fifty years ago, and derivative 4 was prepared twenty years ago [28] , there is only spare data on their biological activities, with binding affinities and selectivities at MOP, DOP and KOP receptors not yet reported. Herein, we also describe the synthesis and biological characterization of a new N-substituted derivative of morphine, N -phenylpropylnormorphine ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Investigations of N-Substituent Variation in Morphine and Oxymorphone: Opioid Receptor Binding, Signaling and Antinociceptive Activity

et al. 2014

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Morphine and structurally related derivatives are highly effective analgesics, and the mainstay in the medical management of moderate to severe pain. Pharmacological actions of opioid analgesics are primarily mediated through agonism at the µ opioid peptide (MOP) receptor, a G protein-coupled receptor. Position 17 in morphine has been one of the most manipulated sites on the scaffold and intensive research has focused on replacements of the 17-methyl group with other substituents. Structural variations at the N-17 of the morphinan skeleton led to a diversity of molecules appraised as valuable and potential therapeutics and important research probes. Discovery of therapeutically useful morphine-like drugs has also targeted the C-6 hydroxyl group, with oxymorphone as one of the clinically relevant opioid analgesics, where a carbonyl instead of a hydroxyl group is present at position 6. Herein, we describe the effect of N-substituent variation in morphine and oxymorphone on in vitro and in vivo biological properties and the emerging structure-activity relationships. We show that the presence of a N-phenethyl group in position 17 is highly favorable in terms of improved affinity and selectivity at the MOP receptor, potent agonism and antinociceptive efficacy. The N-phenethyl derivatives of morphine and oxymorphone were very potent in stimulating G protein coupling and intracellular calcium release through the MOP receptor. In vivo, they were highly effective against acute thermal nociception in mice with marked increased antinociceptive potency compared to the lead molecules. It was also demonstrated that a carbonyl group at position 6 is preferable to a hydroxyl function in these N-phenethyl derivatives, enhancing MOP receptor affinity and agonist potency in vitro and in vivo. These results expand the understanding of the impact of different moieties at the morphinan nitrogen on ligand-receptor interaction, molecular mode of action and signaling, and may be instrumental to the development of new opioid therapeutics.

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N-Substituted Epoxymorphinans

Cited by 38 publications

References 5 publications

N-Demethylation of Alkaloids

N-Demethylation of Alkaloids

Synthesis of Potential Haptens with Morphine Skeleton and Determination of Protonation Constants

Pharmacological Investigations of N-Substituent Variation in Morphine and Oxymorphone: Opioid Receptor Binding, Signaling and Antinociceptive Activity

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