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.
Highlights
Topics AbstractIntroduction Neurotransmitter (NT) Reuptake Inhibitors Serotonin-Norepinephrine Reuptake Inhibitors Imipramine and Amitriptyline Clomipramine Venlafaxine Doxepin Selective Norepinephrine Reuptake Inhibitors Maprotiline Atomoxetine Selective Serotonin Reuptake Inhibitors
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Imatinib contains a heterocyclic tertiary methylamino moiety, which is metabolized by CYP3A4 oxidative N-demethylation to give N-desmethylimatinib, which is of similar potency to the parent drug [191,192,193]
Summary
Introduction Neurotransmitter (NT) Reuptake Inhibitors Serotonin-Norepinephrine Reuptake Inhibitors Imipramine and Amitriptyline Clomipramine Venlafaxine Doxepin Selective Norepinephrine Reuptake Inhibitors Maprotiline Atomoxetine Selective Serotonin Reuptake Inhibitors. IntrodPuoctteinotnial Drug Candidates (Metabolite Drugs) clic teArtlkiaTyrelyratmoianirenyso-,AamrlkoeyiceloatimNmesm-i,Oneooxint-ihMdienaortdiioeorptnuyeg-OnCmfcohonalteianciunaillneipsghoDfartviuacgr(isoeucsonpdhaarrymoarcot3el2ortgiaicrayl)c, loarshseest.eTrohceyirbasicity and polarity are essential for drug action They are found in antidepressants, antihistamines, narcotic anaClgoensciclus,slioocnasl anesthetics, as well as other dru33g classes. Hydroxylation of the alkyl groups at the carbon that is linked to the nitrogen atom [1]. Tertiary amines are dealkylated in a similar way by consecutive hydroxylation of the alkyl groups at the carbon that is linked to the nitrogen atom [1]. Depending on their class, alkylamino moieties interact with receptors or enzymes Molecules 2021, 26, x FOR PEER REVvIEiaWhydrogen bonding, ion-dipole, ion-ion and van der Waals bindings as depic4toefd41in. Phenolic hydroxy groups (OH) are conjugated by glucuronic acid in phase II
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