ABSTRACT
(Z)-3-(4-Bromophenyl)-3-(3-pyridyl)allylamine (CPP 200) is transformed to the corresponding chloroimine by hypochlorite ion (ClO-) formed in the presence of myeloperoxidase. A scheme for this transformation is given. The influence of various compounds on this process has been studied. Cysteamine, cysteine and 6-chloro-3-hydrazino-pyridazine inhibited the transformation of CPP 200, while some p-hydroxyphenyl derivatives increased the rate of transformation of CPP 200. The increase seen on addition of the p-hydroxyphenyl derivatives is not a chloride-dependent reaction. Various mechanisms for the inhibiting effect as well as for the activating effect on the transformation of CPP 200 are discussed.
Subject(s)
Peroxidase/metabolism , Zimeldine/analogs & derivatives , Acetaminophen/pharmacology , Chlorides/metabolism , Chromatography, Thin Layer , Cysteamine/pharmacology , Cysteine/pharmacology , Gas Chromatography-Mass Spectrometry , Hypochlorous Acid/metabolism , Magnetic Resonance Spectroscopy , Parabens/pharmacology , Peroxidase/chemistry , Phenylacetates/pharmacology , Phenylpropionates/pharmacology , Pyridazines/pharmacology , Spectrophotometry, Ultraviolet , Substrate Specificity , Zimeldine/chemistry , Zimeldine/metabolismABSTRACT
A preliminary analysis of a study of the bioavailability and pharmacodynamics of chlormethiazole in healthy young and elderly volunteers has been performed. The bioavailability assessed by a stable isotope method and the pharmacodynamic effects assessed by psychometric tests were found not to differ between the two age groups.
Subject(s)
Chlormethiazole/blood , Administration, Oral , Adult , Aged , Arousal/drug effects , Attention/drug effects , Biological Availability , Chlormethiazole/pharmacology , Female , Humans , Infusions, Parenteral , Kinetics , Male , Metabolic Clearance Rate , Middle Aged , Psychomotor Performance/drug effectsABSTRACT
Analogues of the antidepressant agent zimelidine [6, (Z)-3-(4-bromophenyl)-N,N-dimethyl-3-(3-pyridyl)allylamine], a selective inhibitor of neuronal 5-hydroxytryptamine reuptake, were synthesized by several routes with the aim of obtaining compounds having a cis configuration (with respect to pyridyl and allylamine). Two methods utilized suitably substituted benzoylpyridines as starting materials. In two other routes, the bromine in 6 was either directly displaced (CN) or converted via the corresponding lithio derivative to H, Cl, I, Me, SiMe3, and SMe. The configurations were determined by UV, 1H NMR, and lanthanide-induced shifts in 1H NMR. The compounds were evaluated as uptake inhibitors by measuring the accumulation of [3H]noradrenaline and 5-hydroxy[14C]tryptamine in mouse brain slices (in vitro and in vivo). Para substitution favored 5-hydroxytryptamine activity and ortho substitution favored NA activity in the cis series. The in vitro effect on 5-hydroxytryptamine was rather insensitive to variations in the para substituent, whereas pronounced effects in vivo were observed only with Cl, Br (6), and I.
