Metabolic N-Dealkylation and N-Oxidation as Elucidators of the Role of Alkylamino Moieties in Drugs Acting at Various Receptors

Abstract

Metabolic reactions that occur at alkylamino moieties may provide insight into the roles of these moieties when they are parts of drug molecules that act at different receptors. N-dealkylation of N,N-dialkylamino moieties has been associated with retaining, attenuation or loss of pharmacologic activities of metabolites compared to their parent drugs. Further, N-dealkylation has resulted in clinically used drugs, activation of prodrugs, change of receptor selectivity, and providing potential for developing fully-fledged drugs. While both secondary and tertiary alkylamino moieties (open chain aliphatic or heterocyclic) are metabolized by CYP450 isozymes oxidative N-dealkylation, only tertiary alkylamino moieties are subject to metabolic N-oxidation by Flavin-containing monooxygenase (FMO) to give N-oxide products. In this review, two aspects will be examined after surveying the metabolism of representative alkylamino-moieties-containing drugs that act at various receptors (i) the pharmacologic activities and relevant physicochemical properties (basicity and polarity) of the metabolites with respect to their parent drugs and (ii) the role of alkylamino moieties on the molecular docking of drugs in receptors. Such information is illuminative in structure-based drug design considering that fully-fledged metabolite drugs and metabolite prodrugs have been, respectively, developed from N-desalkyl and N-oxide metabolites.

Light‐Induced Dealkylation of Benzamides in Aqueous Solution

“…[1][2][3][4] It is also one of the specific reactions of cytochrome P450, which is involved, inter alia, in the metabolism of N-containing drugs. [5][6][7] High activity of natural systems in N-dealkylation reactions has been successfully imitated in synthetic chemistry. In particular, the dealkylation of amines has been widely adapted, [8][9][10] giving access to many N-containing compounds, mostly via reaction with cyanogen bromide [11,12] or oxidation [13][14][15] .…”

Stability‐indicating liquid chromatography method development for assay and impurity profiling of amitriptyline hydrochloride in tablet dosage form and forced degradation study

“…The reported methods were reviewed and tested, but the desired separation and stable retention time were not achieved for impurity C in any of the conditions (Table 2; Ali & Nourolhoda, 2008; Eh‐Haj, 2021; El‐Houssini & Zawilla, 2014; Kasagić‐Vujanović & Jančić‐Stojanović, 2019; Luana et al, 2018; Manorama et al, 2015; Neeli & Haritha, 2013; Rafael et al, 2008; Ramadevi et al, 2018; Sejal & Patel, 2009; Sultana & Vandana, 2018). Thus, it was decided to develop a suitable test method for the separation and quantitative determination of AMT and its organic impurities.…”

“…A literature search revealed that many chromatographic methods were reported for the estimation of the assay and organic impurities of AMT individually and combined with some other drugs, but the reported liquid chromatography methods for AMT were not sufficiently robust and reproducible when they were intended to be used for the organic impurity testing of AMT (Ali & Nourolhoda, 2008;Eh-Haj, 2021;El-Houssini & Zawilla, 2014;Kasagi c-Vujanovi c & Janči c-Stojanovi c, 2019;Luana et al, 2018;Manorama et al, 2015;Neeli & Haritha, 2013;Rafael et al, 2008;Ramadevi et al, 2018;Sejal & Patel, 2009;Sultana & Vandana, 2018). Thus, the authors…”

“…A literature search revealed that many chromatographic methods were reported for the estimation of the assay and organic impurities of AMT individually and combined with some other drugs, but the reported liquid chromatography methods for AMT were not sufficiently robust and reproducible when they were intended to be used for the organic impurity testing of AMT (Ali & Nourolhoda, 2008; Eh‐Haj, 2021; El‐Houssini & Zawilla, 2014; Kasagić‐Vujanović & Jančić‐Stojanović, 2019; Luana et al, 2018; Manorama et al, 2015; Neeli & Haritha, 2013; Rafael et al, 2008; Ramadevi et al, 2018; Sejal & Patel, 2009; Sultana & Vandana, 2018). Thus, the authors developed a stability‐indicating method for the quantitative determination of AMT and its four organic impurities (named as impurity A, amitriptyline‐related compound A; impurity B, amitriptyline‐related compound B; impurity C, nortriptyline; and impurity D, cyclobenzaprine) in the drug substance and drug product of AMT (Scheme 1).…”

Investigation of Bemethyl Biotransformation Pathways by Combination of LC–MS/HRMS and In Silico Methods

“…However, BioTransformer did not predict the formation of this compound, and, therefore, we still do not have enough evidence to suggest the type of the cytochrome involved in this reaction. Compound Т1 can undergo oxidative dealkylation by a mechanism analogous to the mechanism of oxidative N-dealkylation [26]. The dealkylation product is metabolite M1 (Figure 8), which was identified by mass spectrometry.…”