Microsomal N-oxidation of long chain N,N-dimethylalkylamines: Quantitative structure-activity relationships

Abstract

N,N-Dimethylalkylamines CmH2m+1N(CH3)2 (m = 4 to 18) undergo in vitro N-oxidation to the corresponding amine oxides by mouse liver microsomes. The relative oxidisability of these compounds is parabolically dependent on structural and physico-chemical characteristics (with a maximum at m 12) and is controlled by at least three factors: lipophilicity, stereochemistry and the nucleophilicity of the compounds under evaluation. The results from the QSAR study support this multifactorial view.

QSAR study on species differences in microsomal N-oxygenation of N,N-dimethylalkylamines

“…We have shown in our previous study on this topic that there are at least three characteristics of N,N-dimethylalkylamines influencing their ROA with mouse microsomes: the lipophilicity, the stereochemistry and the nucleophilicity. This seems to also hold for the present case (Devinsky & Gorrod 1987).…”

“…The results of our study ( Table I, 2) using the same variable as before (Devinsky & Gorrod 1987) clearly shows the parabolic course of ROA upon the structural and physicochemical parameters characterizing the substrates and products. The resulting curves are smooth and the data well fit the equations for a parabola as proved by statistical analysis (all functional relationships are statistically significant at a high confidence level) (Craig et al 1971).…”

“…However, as pointed out by Ziegler (l98S), there have been no studies that show significant quantitative differences in the purified liver mono-oxygenase from different species. This is a continuation of our earlier work (Devinsky & Gorrod 1987) on the influence of substrate structural changes upon the microsomal N-oxidizability of N,N-dimethylalkylamines. The purpose of this communication is to report results from a study using QSAR methodology on the effect of structure and some physico-chemical properties (lipophilicity, nucleophilicity) of substrates and products upon the relative rates of N-oxide formation using a series of N,N-dimethylalkylamines (CmH2,+1N(CH& m = 4 to 18) with hepatic microsomal homogenates prepared from various species.…”

“…Chemicals. N,N-Dimethylalkylamines and the corresponding Noxides were prepared in our laboratories according to reported methods (Devinsky et a1 1978(Devinsky et a1 , 1982 Enzyme preparation, incubation, extraction, isolation, and identification of substrates and products were carried out as described previously (Devinsky & Gorrod 1987).…”

“…)-l per 20 min]' Purified pig liver microsomal mixed function amine oxidase, (mol dm -3 (mg prot. )-' min -') Calculated from eqn 2(Devinsky & Gorrod 1987) ' Calculated from relationship log K$D = f (m) Calculated according toRekker (1977) [K] For the corresponding N-oxides taken fromDevinsky et a1 (1985), (dm' mol-I) GreyhoundAt 105 kN m…”