Formation of quaternary amines by N- methylation of azaheterocycles with homogeneous amine n-methyltransferases

Crooks, Peter A.; Godin, C.; Damani, L. A.; Ansher, Sherry S.; Jakoby, William B.

doi:10.1016/0006-2952(88)90426-1

Cited by 27 publications

(10 citation statements)

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“…This might indicate that arylalkylimidazoles are methylated by the same or a closely related enzyme. The assumption receives support from the pH-dependency of the reaction: the highest methyltransferase activity, when tested with medetomidine as substrate, was observed between pH 8.0 and 7.8, the pH-optimum of the homogeneous amine N-methyltransferases (Lyon & Jakoby 198 1;Crooks et al 1988). Below this point the activity slowly decreased.…”

Section: Discussionmentioning

confidence: 89%

“…Detomidine, medetomidine and dexmedetomidine were methylated by the post-microsomal supernatant, but not by the microsomal fraction, of rat kidney. The cytosolic location is a common feature of most drug metabolizing Nmethyltransferases (Borchardt 1980;Lyon & Jakoby 198 I;Crooks et al 1988). Methylation of arylalkylimidazoles by the liver cytosol was only moderate, whereas histamine was effectively converted.…”

Section: Discussionmentioning

confidence: 99%

“…As structural analogues of histamine 4-arylalkyl-1Himidazoles are possible substrates of histamine N-methyltransferase, an enzyme active also in the brain (Borchardt 1980). Some cytosolic N-methyltransferases in the liver are known to methylate imidazole (Crooks et al 1988) and could also be involved.…”

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confidence: 99%

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Tissue‐Specificity of Hydroxylation and N‐Methylation of Arylalkylimidazoles

Salonen¹

1991

Pharmacology & Toxicology

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Hydroxylation and N-methylation of three potent alpha 2-adrenoceptor agonists detomidine, medetomidine and dexmedetomidine by rat brain, kidney, liver and lung were studied in vitro. NADPH-dependent hydroxylation of the 3'-methyl group was catalyzed mainly by the microsomal fraction of liver. Monooxygenation by the other tissues was negligible. The hepatic monooxygenase reaction was characterized by high affinity (Km 5.5-9.8 microM) and low capacity (Vmax 29-66 pmol/min. per mg protein). Statistically significant (P less than 0.05) differences between the Km and Vmax values of medetomidine and dexmedetomidine were observed suggesting stereoselective oxidation of the drug molecule. N-Methylation of the arylalkylimidazoles occurred mainly in the cytosolic fraction of the kidney. With S-adenosylmethionine as the methyl donor, the transferase activities in other tissues were less than 10% of the specific activity of the renal enzyme (about 7 pmol/min. per mg protein for medetomidine). Even the renal enzyme showed a relatively low capacity (Km 250-300 microM and Vmax 15-33 pmol/min. per mg protein). Different tissue distributions of the arylalkylimidazole N-methyltransferase and histamine N-methyltransferase suggest that they are two distinct enzyme species. Based on these results, aliphatic hydroxylation is the major (metabolic) elimination mechanism of the arylalkylimidazole drugs, and liver is the principal eliminating organ. The importance of N-methylation is diminished by its low capacity and probable regeneration of the parent drug by demethylation.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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Tissue‐Specificity of Hydroxylation and N‐Methylation of Arylalkylimidazoles

Salonen¹

1991

Pharmacology & Toxicology

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“…Besides these endogenous compounds, a significant number of exogenous amines are N-methylated. In contrast, amine NMT exists as two or more isozymes with broad and overlapping substrate specificities which include primary and secondary aromatic amines as well as aromatic azaheterocycles [25] [26]. This Figure presents an Enzyme Identity Card of NNMT and HNMT, both of which are cytosolic and are expressed in the liver and in a number of other organs.…”

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confidence: 99%

“…4.15). Indeed, amine NMT appears as the major but not only enzyme acting on pyridine (4.35; R ¼ H) and pyridine analogues, 4.35 (R = H) [26] [30]. In other words, nicotinamide NMT is a useful detoxification enzyme, but its marked interindividual variability also implies that detoxification of pyridine-type compounds is reduced in a fraction of the human population.…”

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confidence: 99%

ChemInform Abstract: The Biochemistry of Drug Metabolism — An Introduction. Part 4. Reactions of Conjugation and Their Enzymes

Testa

Kraemer

2009

ChemInform

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This Part 4 of our biochemical introduction to drug metabolism [1 -4] presents the reactions of conjugation and their enzymes. As we shall see, reactions of conjugation are also a major focus of interest in the metabolism of drugs and other xenobiotics. Books specifically dedicated to conjugation reactions are rare [5], but much recent information can be found in book chapters (e.g.,For a reaction of conjugation to occur, a suitable functional group must be present in the substrate, which will serve as the anchoring site for an endogenous molecule or moiety such as CH 3 , sulfate, glucuronic acid, or glutathione. Conjugation reactions are thus synthetic (i.e., anabolic) reactions whose products are of modestly to markedly higher molecular weight than the corresponding substrate. As for the anchoring group, it can either be present in a xenobiotic or be created by a functionalization reaction. In other words, reactions of conjugation are able to produce first-generation as well as later-generation metabolites. We, therefore, consider as unfelicitous the term of phase II reactions commonly used to designate conjugations.A first issue when discussing reactions of conjugation will be to offer a clear definition. As we shall see, a number of criteria exist, all of which show some degree of fuzziness, and only one of which must necessarily be met. This has indeed led to some confusion with reactions of hydrolysis, which some biochemists have viewed as conjugation. We oppose such a view for reasons previously explained [3]. To repeat what we stated, reactions of hydrolysis are not catalyzed by transferases (EC 2) but by hydrolases (EC 3) [8], and water is not an endogenously synthesized molecule or moiety linked covalently to a cofactor.Reactions of conjugation, like the reactions of functionalization we saw in Parts 2 and 3, act on exogenous substrates (i.e., xenobiotics [1]) as well as endogenous substrates (i.e., endobiotics). This dual functionality may create a potential for metabolic interaction between a drug and an endogenous substrate, a frequently overlooked mechanism of toxicity. Thus, there may be competitive affinity for the catalytic site of an endobiotic-metabolizing enzyme, or there may be competition for the limited supply of a cofactor. A typical example of the latter case is found with

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Principles of Drug Metabolism

Testa

Soine

2003

Burger's Medicinal Chemistry and Drug Discovery

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The focus of this chapter is mainly on drug metabolism reactions and connected information of significance to medicinal chemists. The types, selectivities, and consequences of drug metabolism are presented in the introduction. Oxidoreductases are discussed in the next section, together with a systematic and extensive treatment of the chemical groups they target and the functionalization reactions they catalyze. Particular attention is paid to cytochromes P450 and their multiplicity, specificities, and relative importance. Section 3 is dedicated to the transferases and the conjugation reactions they catalyze, e.g., glucuronidation and glutathione conjugation. The various biological factors influencing drug metabolism are examined in Section 4. These are subdivided into interindividual factors (that depend on the genome) and intraindividual factors (that can vary with time or because of external influences). The last section, which is particularly close to the interests of medicinal chemists, discusses structure‐metabolism relationships, prodrug design, and toxophoric groups.

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Formation of quaternary amines by N- methylation of azaheterocycles with homogeneous amine n-methyltransferases

Cited by 27 publications

References 19 publications

Tissue‐Specificity of Hydroxylation and N‐Methylation of Arylalkylimidazoles

Tissue‐Specificity of Hydroxylation and N‐Methylation of Arylalkylimidazoles

ChemInform Abstract: The Biochemistry of Drug Metabolism — An Introduction. Part 4. Reactions of Conjugation and Their Enzymes

Principles of Drug Metabolism

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