No abstract

The effect of incorporation of an eleostearoyl group into molecules of aralkylhydrazines on their monoamine oxidase inhibitory potency was investigated in vitro and in vivo. The results showed that on a molar basis the hydrazides possessed an in vitro potency lower than and an in vivo potency and acute toxicity comparable to those of the corresponding aralkylhydrazines. The sequence of the relative potency of aralkylhydrazines and their hydrazides was similar. The overall pharmacological profile indicated that these aralkylhydrazines retained their monoamine oxidase inhibitory properties when the free hydrazine nitrogen was acylated with an eleostearoyl group.

leveled off) but involves the other features of the molecule, then KI, kc, and kwill be independent of X. On the other hand, kz will be highly dependent upon X and this dependence will only show up when k2 S kc , This scheme also might involve a pentacovalent intermediate.Although this kind of explanation is ad hoc, it should be noted that reversible complexes and substrate-induced conformational changes have played a dominant role in enzyme theory for many years.''?"In a previous study," it was found that the curvature that sets in sharply at pK, = 7.0 did not occur when the leaving group contained a quaternary ammonium function so that these compounds were decidedly more reactive than would be anticipated from the pK, of their leaving groups. The rationalization offered above would suggest that the conformational change occurs more rapidly when the inducing compound contains a cationic amine function. There is spectral evidence that quaternary amines change the conformation of acetyl~holinesterase.'~ We note that with few exceptions the ring compounds re-act less rapidly than the open-chain analogs but the distinction is not great enough to account for the poor inhibitory properties of the fluoride and p-nitrophenolate in the ring series.The syntheses of five N-substituted eleostearic acid hydrazides are described: N-isopropyl-cu-eleostearoyl hydrazide, N-benzyl*-eleostearo yl hydrazide) N-phenethyl-0-eleostearo yl hydrazide, Nd-methylphenethy 1-0-eleostearoyl hydrazide, and N-0-methylphenethyla-eleostearoyl hydrazide. The compounds were investigated for their ability to inhibit monoamine oxidase in vitro and to elevate the brain monoamines in mice. The results showed that these compounds were active monoamine oxidase inhibitors with their slightly lower in vitro activity but comparable in vivo activity in comparison with the corresponding monosubstituted hydrazines.The monosubstituted hydrazines such as alkyl-and aralkylhydrazines have provided many potent monoamine oxidase (MAO) inhibitors from which phenelzine has emerged as a clinically used antidepressant.' Pheniprazine, benzylhydrazine, and isopropylhydrazine are among the most potent MA0 inhibitors but are barred from clinical use because of high zine with 5-methyl-3-isoxazolylcarboxylic acid has produced another currently used hydrazine antidepressant, isocarboxazide, with MA0 inhibitory activity but reduced toxicity.' Iproniazide, the isonicotinic acid acylated isopropylhydrazine, the first MA0 inhibitor antidepressant: also possesses an activity comparable to isopropylhydrazine with less toxicity. The present work was to synthesize some N-substituted hydrazides by acylating some of the most potent monosubstituted hydrazines with a-eleostearic acid (94s-l l-trans-13-trans-octadecatrienoic acid) and 0eleostearic acid (9-trans-1 1 -trans-13-trans-octadecatrienoic Acylation of benzylhydra-?These experiments were supported in part by a grant from the Research Institute of Pharmaceutical Sciences of the University of Mississippi and in part by a grant (5 R0...

No abstract

No abstract