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At least 109 records · Page 6Linked to original sources
PubMed1985

Mechanism of inactivation of monoamine oxidase by 1-phenylcyclopropylamine.

1-Phenylcyclopropylamine (1-PCPA) is shown to be a mechanism-based inactivator of mitochondrial monoamine oxidase (MAO). The strained cyclopropyl ring is important to inactivation since alpha,alpha-dimethylbenzylamine, the acyclic analogue of 1-PCPA, is neither an inactivator nor a substrate of MAO. Two different pathways occur during inactivation by 1-PCPA, both believed to be derived from a common intermediate. One pathway leads to irreversible inactivation of the enzyme and a 1:1 stoichiometry of radioactivity to the active site when 1-[phenyl-14C]PCPA is used as the inactivator; the other pathway results in a covalent reversible adduct. Three organic reactions are carried out on the irreversibly labeled enzyme in order to determine the structure of the active site adduct. Sodium boro[3H]hydride reduction results in the incorporation of 0.73 equiv of tritium, suggesting a carbonyl functionality. Baeyer-Villiger oxidation followed by saponification gives 0.8 equiv of phenol, indicating the presence of a phenyl ketone. Treatment of the labeled enzyme with hydroxide produces acrylophenone, as would be expected from the retro-Michael reaction of beta-X-propiophenone. The identity of X is determined in two ways. The optical spectrum of the flavin cofactor is reduced during inactivation; no reoxidation occurs upon denaturation. Pronase treatment of the radioactively labeled enzyme produces fragments that contain both the radioactivity and the flavin. The X group, therefore, is the flavin. The results of two tests designed to differentiate N5 from C4a attachment to the flavin suggest an N5 adduct. In addition to formation of this stable covalent adduct, another pathway occurs 7 times as often. This alternate reaction of 1-[phenyl-14C]PCPA with MAO produces 7 equiv of [14C]acrylophenone during the course of irreversible inactivation and is believed to arise from formation of the same type of adduct as described above except that X is something other than the N5-flavin (Y). Upon denaturation of this labeled enzyme, the flavin is completely oxidized when most of the radioactivity is still bound to the enzyme. This indicates that Y is not a C4a-flavin adduct and suggests attachment to an active site amino acid residue. More facile elimination of Y from this beta-substituted propiophenone adduct would give acrylophenone on the time scale of the inactivation. Treatment of the reversible adduct with sodium borohydride prior to denaturation prevents release of radioactivity.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

[(Alkylamino)methyl]acrylophenones: potent and selective inhibitors of the epidermal growth factor receptor protein tyrosine kinase.

[(Alkylamino)methyl]acrylophenones and (alkylamino)propiophenones, bearing a spacer moiety such as the benzyloxy or (benzoylsulfonyl)oxy group in the 4-position, represent a novel class of inhibitors of the epidermal growth factor (EGF) receptor protein tyrosine kinase with a high degree of selectivity versus other tyrosine and serine/threonine kinases. The most active compounds inhibited the EGF receptor protein tyrosine kinase from A431 cell membranes with IC50 values of < 0.5 microM. Derivatives with a benzyloxy substituent in the 4-position of the aromatic ring inhibited both the EGF receptor kinase and the proliferation of an EGF-dependent mouse epidermal keratinocyte cell line (BALB/MK) but were only marginally active in the inhibition of the cellular EGF-dependent tyrosine phosphorylation. Compound 18 inhibited ligand-induced tyrosine phosphorylation and BALB/MK cell proliferation with IC50 values of approximately 100 and 1.21 microM, respectively, and showed antitumor activity in vivo in a nude mouse model. However, the discrepancy between the IC50 values for antiproliferative activity and cellular tyrosine phosphorylation as well as the relatively low tolerability in animals suggests a second site of action of this class of inhibitors. Nevertheless, [(alkylamino)methyl]acrylophenones and (alkylamino)propiophenones may prove to be interesting tools for studying the action of tyrosine kinases.

Animals↗
PubMed1997

Asymmetric Electroreduction of Ketone and Aldehyde Derivatives to the Corresponding Alcohols Using Alcohol Dehydrogenase as an Electrocatalyst.

Asymmetric electroreduction of ketone and aldehyde derivatives was examined for two electrochemical reduction systems using alcohol dehydrogenase (ADH) as an electrocatalyst. The reaction system A is concerned with reduction of substrates catalyzed by ADH coupled with regeneration of cofactors by another enzyme with assistance of methyl viologen as an electron mediator, and the reaction system B is concerned with the use of ADH as the sole enzyme which catalyzes both reduction of substrates and regeneration of cofactors. In the latter case, a redox couple of phenethyl alcohol/acetophenone is used as an electron mediator to induce the reaction. The electrolysis using the system A allowed asymmetric reduction of acetophenone, propiophenone, phenoxy-2-propanone, pyruvic acid, and 2-phenylpropionaldehyde to the corresponding optically active alcohols with the enantiomer excesses (ee) close to 100% and the current efficiencies larger than 92%, and the turnover number of the cofactor higher than 50 was obtained for electrochemical reduction of phenoxy-2-propanone for 30 h. The reaction system B gave 100% ee for reduction of propiophenone, phenoxy-2-propanone, and pyruvic acid. However, the amount of products obtained was very small for reduction of benzoylformic acid, and a low enantiomer excess was obtained for reduction of phenylpropionaldehyde. Discussion is made focusing on what substrates are suitable for asymmetric reduction induced by the reaction system B.

Journal Article↗
PubMed1977

The role played by the extraneuronal system in the disposition of noradrenaline and adrenaline in vessels.

The role played by extraneuronal sites in the disposition of noradrenaline and adrenaline was studied in the saphenous vein and in the mesenteric artery of the dog, taking as parameters the influence of blockade of these sites on the sensitivity to and on the time for half-relaxation (t50) (both in oil and in Krebs solution) of these agonists. Preliminary experiments have shown that the t50 values are not significantly changed by the changes in the height of the contraction provided the contraction is caused by the same concentration of the agonist. The results obtained permit us to conclude that in both vessels the removal of amines depends on the concentrations used. In low (0.023 and 0.23 muM) or in moderately high (2.3 muM) concentrations, adrenaline is removed preferentially by extraneuronal sites, whereas noradrenaline "preferred" neuronal sites. The selectivity of adrenaline for extraneuronal sites was present for such low concentrations that a possible physiological role of these sites in the inactivation of circulating adrenaline must be considered. The results obtained by studying the relaxation in oil in Krebs solution and by using cortexone (60 muM) or U-0521 (dihydroxy-2-methyl propiophenone; 0.1 mM) support the view that, at least in the vein, adrenaline may accumulate in extraneuronal cells and diffuse back into the biophase during the relaxation, thereby slowing the latter. Both in the veins and in the arteries noradrenaline was inactivated more rapidly than adrenaline. The difference in the rate of inactivation of these amines, already observed in controls (when all inactivation pathways are operative) became more marked when both neuronal and extraneuronal sites were blocked. The existence of an important pathway not blocked by cocaine + cortexone + iproniazid which may preferentially inactivate noradrenaline cannot be ruled out.

Animals↗
PubMed1975

Relation between the amount of smooth muscle of venous tissue and the degree of supersensitivity to isoprenaline caused by inhibition of catechol-O-methyl transferase.

The relation between the smooth muscle cell mass of dog saphenous vein strips and the degree of supersensitivity to isoprenaline caused by U-0521 (3,4-dihydroxy-2-methyl propiophenone), an inhibitor of the catechol-O-methyl transferase (COMT), was studied. For the quantitative determination of smooth muscle mass, the thickness of the muscle layer as determined by light microscopy and the maximal shortening induced by supramaximal concentration of phenylephrine were used. After the strips had been contracted by 3x10-6M phenylephrine, a concentration which was able to produce an about 90% maximal contraction, dose-response curves to the relaxant effect of isoprenaline were determined in the absence and in the presence of U-0521 (10-4M). It was observed that U-0521 caused marked supersensitivity to the relaxant effect of isoprenaline (varying between 3 and 81 times), as well as an increase of the maximal relaxation caused by this amine (varying between 7 and 120%). The correlation between these data and the smooth muscle cell mass shows that there was a direct proportionality between these parameters. Oxytetracycline (10-4M), an inhibitor of binding of catecholamines to collagen, did not produce any enhancement of the effects of isoprenaline. It is concluded that COMT is related to smooth muscle cells in this tissue.

Animals↗
PubMed1987

Altered metabolism of [18F]-6-fluorodopa in the hooded rat following inhibition of catechol-O-methyltransferase with U-0521.

[18F]-6-Fluoro-L-DOPA ([18F]DOPA), a tracer for cerebral dopamine in studies utilizing positron emission tomography (PET), is rapidly metabolized by catechol-O-methyltransferase (COMT) in the periphery following intravenous injection to carbidopa-pretreated humans and rats. Experiments were performed to determine the effect of pretreatment with 3',4'-dihydroxy-2-methyl-propiophenone (U-0521), a competitive inhibitor of COMT, on [18F]DOPA metabolism in the carbidopa-pretreated hooded rat. U-0521 (25 mg/kg, i.p.), administered 10 min prior to the [18F]DOPA, served to increase the persistence of [18F]DOPA in plasma over a 2-hr period by decreasing the rate of formation of the peripheral metabolite 3-O-methyl-6-fluorotyrosine (Me[18F]DOPA). This compound passes readily into brain and was the sole [18F]DOPA metabolite observed in cortex and cerebellum. U-0521 produced a short-lasting decrease in Me[18F]DOPA levels in these two tissues. In striatum, decreases in Me[18F]DOPA were found to last at least 90 min. Associated with the elevated availability of [18F]DOPA in plasma produced by U-0521 were 50% increases in striatal [18F]dopamine ([18F]DA) levels and 40% increases in the levels of [18F]dihydroxyphenylacetic acid ([18F]DOPAC) at times between 30 and 90 min following [18F]DOPA injection. Increased decarboxylation of [18F]DOPA in the striatum of U-0521-treated rats resulted in heightened radiocontrast between striatum and other cerebral tissues.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1976

Inhibitory actions of polyphloretin phosphate and related compounds on the response to prostaglandin in the smooth muscle of guinea-pig stomach.

The inhibitory actions of polyphloretin phosphate (PPP) and related compounds, di-4-phloretin phosphate (DPP), PHLORETIN AND TRIHYDROXY PROPIOPHENONE (THPP) on the contractile responses to prostaglandin (PG) and acetylcholine (ACh) in longitudinal smooth muscle of guinea-pig stomach were studied. Of the four inhibitors PPP and DPP showed relatively selective antagonism for PGE1. DPP gave the highest pW2 value against PGE1. These results indicate that DPP is a useful antagonist of PG in smooth muscle, although it slightly inhibits responses to ACh, 5-HT or histamine, and the Ca-induced contracture in K depolarized preparation.

Acetylcholine↗
PubMed1988

The guinea-pig trachea O-methylating system is more effective in modulating beta 2- than beta 1-adrenoceptor-mediated responses to isoprenaline.

Assuming that responses of the guinea-pig trachea to isoprenaline in the presence of atenolol (10 mumol L-1) are exclusively, or at least predominantly, beta 2-adrenoceptor mediated and that responses to isoprenaline in the presence of ICI 118,551 (erythro-DL-1(7-methylindan-4-yloxyl)-3-isopropylaminobut an-2-ol) (1 nmol L-1) are exclusively, or at least predominantly beta 1-adrenoceptor mediated, the influence of inhibition of COMT by U-0521 (dehydroxy-2-methyl propiophenone) (50 mumol L-1) has been compared in both conditions. U-0521 enhanced beta 2-adrenoceptor mediated responses to isoprenaline 3.3-fold, while those mediated by beta 1-adrenoceptors were enhanced only 2.2-fold. It is concluded that in guinea-pig trachea COMT activity is functionally more effective in modulating responses which are mediated by beta 2-adrenoceptors than responses mediated by beta 1-adrenoceptors.

Adrenergic beta-Antagonists↗
PubMed1976

A comparative study of the role played by some inactivation pathways in the disposition of the transmitter in the rabbit aorta and the saphenous vein of the dog.

The aim of this study was to determine the relative importance of neuronal uptake, catechol-O-methyltransferase (COMT) and diffusion in the disposition of endogenous nor-adrenaline (NA) in the rabbit aorta and dog saphenous vein. Helical strips of dog saphenous vein and rabbit aorta were stimulated transmurally, relaxation occurring either in oil or in Krebs-Henseleit solution. The rate of inactivation of NA by various mechanisms was assessed from the decrease in the rate of relaxation after blockade of one or more of these processes. Cocaine was used to inhibit neuronal uptake and COMT was blocked with 3,4-dihydroxy-2-methyl propiophenone. Diffusion out of the tissue was prevented by replacing the Krebs-Henseleit solution in the muscle bath with mineral oil. Neuronal uptake was the primary mechanism of inactivation in the saphenous vein whereas diffusion and COMT appear to be more important in the aorta. The differences in the relative importance of the inactivation mechanisms (neuronal uptake, O-methyltransferase and diffusion) existing between these two vessels are attributed primarily to differing density and distribution of the adrenergic innervation.

Animals↗
PubMed1983

Immunopharmacological studies on mydocalm and related compounds as an antagonist of slow reacting substance of anaphylaxis (SRS-A).

The antagonistic effect of 2,4'-dimethyl-3-piperidino propiophenone hydrochloride (Mydocalm) and its 15 derivatives against the activity of slow reacting substance of anaphylaxis (SRS-A) were examined in vitro. Mydocalm, 2-methyl-3-piperidino-beta-propionaphthone hydrochloride (As-5) and 2,3',4'-trimethyl-3 piperidinopropiophenone hydrochloride (As-14) were found to be potent antagonists to SRS-A. The above three compounds inhibited homologous passive cutaneous anaphylaxis (PCA) in rats and guinea pigs but not heterologous PCA in guinea pigs. As-5 inhibited the release of histamine from and the degranulation of rat mesenterium mast cells. As-14 also showed the inhibition of the degranulation. Mydocalm, however, showed no inhibition of these reactions. Experimental asthma in guinea pigs which were passively sensitized with guinea pig immunoglobulin E antibody was significantly inhibited by p.o. administration of Mydocalm, As-5 or As-14 respectively.

Animals↗
PubMed1975

Positive and negative chronotropic response of the S-A node to oxyfedrine.

Direct perfusion of the sinus node artery under a constant pressure of 100 mmHg was carried out in vagotomized dogs. "Selective" injection of L-3-methoxy-omega-(1-hydroxy-1-phenylisopropylamino) propiophenone hydrochloride (oxyfedrine) into the sinus node artery induced three types of chronotropic response; a pronounced sinus tachycardia, an initial bradycardia followed by sustained tachycarcia, or a definite sinus bradcardia alone. The paradoxical sinus bradycardia induced by oxyfedrine was more pronounced at higher doses of the compound, whereas it was nver produced by the injection of isoproterenol. The oxyfedrine-induced sinus tachycardia, which occurred even in reserpinized preparations, was not suppressed by the treatment with tetrodotoxin, hexamethonium or bretylium, but it was selectively inhibited by propranolol. Atropine, tetrodotoxin or hexamethonium did not prevent the occurrence of sinus bradycardia induced by oxyfedrine, and physostigmine failed to enhance the response. The present study indicates that the oxyfedrine-induced tachycardia is mediated mainly by a direct stimulating action on adrenergic beta-receptors, while the bradycardia appears to be induced by a direct depressant action on the S-A node.

Animals↗
PubMed1979

Structure-activity relationship of 5-hydroxykynurenamine analogues in isolated dog cerebral arteries.

In helically-cut strips of cerebral arteries isolated from dogs, analogues of 5-hydroxykynurenamine (5-HK), including 2-(3'-aminopropyl)-aniline (Cpd. I), 2'-amino-3-dimethylamino-3'-hydroxypropiophenone(CPD. II), 2'-amino-3-dimethylamino-5'-hydroxypropiophenone (Cpd. III) and 2',3-diamino-propiophenone (kynurenamine), caused a dose-related contraction which was antagonized by treatment with methysergide. The potency for inducing contractions was in the order of 5-hydroxytryptamine greater than 5-HK greater than Cpd. III greater than kynurenamine, Cpd. I and Cpd. II. Treatment with the 5-HK analogues antagonized the contractile response to 5-hydroxytryptamine in a dose-dependent manner, the antagonistic potency being in the order of 5-HK greater than Cpd. III greater than kynurenamine, Cpd. II greater than Cpd. I. Alterations in the hydroxy group on the benzene ring and/or radicals of long side chain of 5-HK attenuated the agonistic and antagonistic actions of 5-HK; however, the attenuation of these actions differed. Thus, the radicals appear to be involved in the agonistic and antagonistic actions to a different extent.

Aniline Compounds↗
PubMed1976

The effect of etafenone on the subcellular distribution of calcium and some oligoelements in heart muscle. Ultracytochemical and x-ray microanalytical study.

In order to detect the subcellular localization of calcium in the myocardium of laboratory animals (rats and guinea-pigs) under the influence of 2'-(2-diethylaminoethoxy)-3-phenyl-propiophenone (etafenone, Baxacor) (4 mg, 20 mg and 100 mg/kg body weight) two ultracytochemical methods, with lead acetate and with potassium pyroantimonate, were used. In addition, X-ray microanalysis of myocardial fragments was performed. The correlation of ultrastructural, ultracytochemical and X-ray microanalytical findings provides direct evidence of the hypothesis that etafenone acts on myocardium as a so-called "calcium antagonist". The subcellular targets of etafenone action are mainly the sarcoplasmic reticulum and mitochondria. Etafenone modifies also the concentration of copper, zinc and selenium in myocardium. The effect of etaferone on myocardial calcium and oligoelements appears to be dose-dependent.

Animals↗
PubMed1975

[The effect of oxyfedrine on cardiac performance in coronary patients. Tests using electrocardiographic and metabolic parameters in atrial stimulation].

In 17 patients with coronary heart disease the effects of the beta-active agent L-3-(beta-hydroxy-alpha-methyl-phenethyl-amino)-3'-methoxy-propiophenone (oxyfedrine, Ildamen) were proved at rest and during atrial pacing by measurements of coronary venous O2-saturation, myocardial lactate extraction, angina threshold and ST-segment depression. In 88% oxyfedrine had antianginal effectivity with rise in angina threshold (+11%), reduction of ST-segment depression (--48%) and reduction of lactate production(--63%). The rise in coronary venous O2-saturation ("35%) and the electrocardiographic and metabolic reduction of hypoxic reaction indicate the improvement of nutritional coronary flow. Therefore improvement of myocardial O2-balance is derived from the reduced energy requirement by decrease of heart size and ventricular wall tension and the rise of myocardial O2-supply by coronary dilation in spite of the increased energy requirement by ascending contractility. Conclusively the application of oxyfedrine is preferred in coronary heart disease with simultaneous congestive heart failure.

Adult↗
PubMed1975

[Pharmacologic effects in combined use of oxyfedrine and beta-acetyldiogoxin].

In guinea pigs the toxic effect of beta-acetyldigoxin was not increased by simultaneously administered 3-(beta-hydroxy-alpha-methyl-phenethyl-amino)-3'-methoxy-propiophenone (oxy-fedrine). There was no evidence of a potentiation of the glycoside effect by the combination with oxyfedrine (ildamen-Novodigal). The threshold dose for arrhythmia was increased: typical glycoside tachyarrhythmias only occurred after higher infused doses. In anesthetized dogs with heart failure by overdosed pentobarbital, the therapeutic effects of beta-acetyldigoxin were sustained and enhanced by oxyfedrine.

Animals↗
PubMed1975

[Stability of oxyfedrine in pharmacological experiments in vitro].

15% of L-3-(beta-hydroxy-alpha-methyl-phenethyl-amino)-3'-methoxy-propiophenone-hydrochloride (oxyfedrine [OF]; ildamen¿) are degradated in Krebs-Henseleit solution under conditions which are necessary for recording a complete concentration-effect curve on guinea-pig papillary muscle (total time max. 100 min). Norephedrine and 3-methoxyacrylophenone are qualitatively analysed as products of degradation by thin-layer chromatography (TLC). Secondary reaction products of the primary degradation are not detectable under these conditions. The quantitative analysis of oxyfedrine, norephedrine and 3-methoxyacrylophenone was carried out by spectrophotometry. Comparatively oxyfedrine and norephedrine were analysed by direct quantitative TLC (measuring of reflectance). The same results were obtained, in principle, by both methods. The importance of this relatively slow degradation for pharmacological in vitro experiments on the mode of action of oxyfedrine is pointed out.

Chromatography, Thin Layer↗