Oxidative N-Dealkylation of <i>p</i>-Cyclopropyl-<i>N,N</i>-dimethylaniline. A Substituent Effect on a Radical-Clock Reaction Rationalized by Ab Initio Calculations on Radical Cation Intermediates

Chen, Hao; Groot, Marcel J. de; Vermeulen, Nico; Hanzlik, Robert P.

doi:10.1021/jo9709209

Cited by 34 publications

(25 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cytochrome P450 enzymes are hepatic heme proteins that catalyse the in vivo oxidative N-dealkylation of tertiary amines. The exact mechanism of this process remains uncertain [60]. Numerous studies have attempted to mimic P450 N-demethylation in the laboratory environment [61][62][63][64][65].…”

Section: Biochemical N-demethylation Methodsmentioning

confidence: 99%

N-Demethylation of Alkaloids

Thavaneswaran

McCamley

Scammells

2006

Natural Product Communications

View full text Add to dashboard Cite

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.

show abstract

Section: Biochemical N-demethylation Methodsmentioning

confidence: 99%

N-Demethylation of Alkaloids

Thavaneswaran

McCamley

Scammells

2006

Natural Product Communications

View full text Add to dashboard Cite

show abstract

“…This assumption was supported by the finding that electron rich pyridine derivatives, even though being more potent to inhibit adenyl-cyclase in vitro than their electron deficient pyridine counterparts, displayed, in general, much weaker 5-HT 1A agonist activity in vivo. 23 The mechanism postulated for the benzylic C-N bond cleavage in compounds of type 4, catalyzed by oxido-reductases, involved a nitrogen radical cation in the first step ( Figure 1). Thus, we reasoned that an electronegative fluorine atom 24 in the -position to the benzylic amino function should (1) retard the oxidation-dependent processes by raising the redox potential of the secondary amino function (E N •• / N +• ) and (2) facilitate absorption by reducing the pK a of the secondary amine 25 and increasing the lipophilicity of the ligand.…”

Section: Resultsmentioning

confidence: 99%

Novel Derivatives of 2-Pyridinemethylamine as Selective, Potent, and Orally Active Agonists at 5-HT_1A Receptors

et al. 1999

View full text Add to dashboard Cite

The aim of this work was to improve the oral bioavailability of a recently discovered, novel structural class of 5-HT 1A receptor agonists: aryl-{[4-(6-R-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl-methanone. Incorporation of a fluorine atom in the -position to the amino function in the side chain led to analogues that exhibited, in general, enhanced and longlasting 5-HT 1A agonist activity in rats after oral administration. Location of the fluorine atom at the C-4 position of the piperidine ring was the most favorable, and among the various substituents tested, the ability of the fluorine was unique in improving the oral activity of this family of ligands. Thus, the derivatives 39, 46, and 61 bound with higher affinity and selectivity to 5-HT 1A receptors (versus dopaminergic D 2 and adrenergic R 1 receptors) and displayed more potent 5-HT 1A agonist activity in vitro and in vivo than their C-4 desfluoro analogues. To examine the relationship between the conformation of the pharmacophore and the level of agonistic activity of this type of ligand, we synthesized a series of 3-chloro-4-fluorophenyl-(4-fluoro-4{[(5-(H or CH 3 )-6-R-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl-methanone derivatives and found that the combination of a 5-methyl and a 6-methylamino substituent on the pyridine ring synergistically affected their 5-HT 1A agonist properties. Thus, the 3-chloro-4-fluorophenyl-(4-fluoro-4{[(5-methyl-6-methylamino-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl-methanone 40 behaved as a more potent 5-HT 1A receptor agonist in vitro and in vivo than its 5-unsubstituted analogue 38. The antidepressant potential of the lead compounds 40, 45, and 54 was examined by means of the forced swimming test (FST) in rats. The results indicated that, after a single oral administration, these compounds inhibited immobility in the FST more potently and more extensively than the clinically used antidepressant imipramine. Thus, 40, 45, and 54 are potent, orally active 5-HT 1A receptor agonists with marked antidepressant potential.

show abstract

“…35 These two examples show that, in the presence of CYP450 isozymes, the arylcyclopropane moiety is metabolically more stable than a methylether or a dimethylamine.…”

Section: Methodsmentioning

confidence: 99%