Biomedical subjects

R G Micetich

Publications and source records attributed to R G Micetich.

50 records · Page 3Linked to original sources

PubMed1987

Neurochemical and neuropharmacological properties of 4-fluorotranylcypromine.

1. The 4-fluoro analogue of the monoamine oxidase-inhibiting antidepressant tranylcypromine was compared to the parent drug with regard to the following: inhibition of monoamine oxidases A and B in vitro and ex vivo; levels of both drugs in brain, liver, and blood after injection of equimolar doses; and effects on brain levels of the amines 2-phenylethylamine, tryptamine, norepinephrine, dopamine, and 5-hydroxytryptamine. 2. 4-Fluorotranylcypromine was found to be 10 times more potent than tranylcypromine at inhibiting monoamine oxidases A and B in vitro in rat brain homogenates. 3. After administration (0.1 mmol/kg, ip), 4-fluorotranylcypromine attained higher brain and liver levels and provided greater availability than did tranylcypromine after the injection of an equimolar amount. 4. At the dose employed, the ex vivo monoamine oxidases A and B inhibitory profiles in brain and liver over a 24-hr period following tranylcypromine and 4-fluorotranylcypromine treatment were not different from each other. 5. Although the drugs had similar effects on inhibition of brain MAO ex vivo, they differed from one another at several time intervals in the increases in concentrations of 2-phenylethylamine, tryptamine, norepinephrine, dopamine, and 5-hydroxytryptamine produced in brain. 6. In conclusion, fluorination of tranylcypromine in the 4 position of the phenyl ring produced a drug which was more potent than the parent drug at inhibiting MAO in vitro and attained higher levels in brain than did tranylcypromine itself after intraperitoneal injection of equimolar amounts of the drugs. 4-Fluorotranylcypromine increased the concentrations of trace amines, catecholamines, and 5-hydroxytryptamine in brain at most time intervals following intraperitoneal injection, and at some time intervals there were differences from tranylcypromine with regard to the amine concentrations produced.

Amines↗

PubMed1987

Synthesis and beta-lactamase inhibitory properties of 2 beta-[(1,2,3-triazol-1-yl)methyl]-2 alpha-methylpenam-3 alpha-carboxylic acid 1,1-dioxide and related triazolyl derivatives.

Benzhydryl 2 beta-[(1,2,3-triazol-1-yl)methyl]-2 alpha-methylpenam- 3 alpha-carboxylate 1,1-dioxide was prepared by heating benzhydryl 2 beta-(azidomethyl)-2 alpha-methylpenam-3 alpha-carboxylate 1,1-dioxide with (trimethylsilyl)acetylene. The ester group was removed by hydrogenolysis to give sodium 2 beta-[(1,2,3-triazol-1-yl)methyl]-2 alpha-methylpenam-3 alpha-carboxylate 1,1-dioxide (3i, YTR-830), which was found to be a potent inhibitor of various bacterial beta-lactamases. A series of related compounds was prepared in a similar way, and all of these compounds show excellent beta-lactamase inhibitory properties.

Ampicillin↗

PubMed1986

Detection and quantitation of a ring-hydroxylated metabolite of the antidepressant drug tranylcypromine.

The formation of p-hydroxytranylcypromine from intraperitoneally injected tranylcypromine was confirmed using two types of experiments. In the first, tranylcypromine levels were shown to be increased in brains of rats pretreated with agents known to be inhibitors of ring hydroxylation compared to rats pretreated with physiological saline. For the second set of experiments, p-hydroxytranylcypromine was identified in brain and urine (following intraperitoneal injection) by derivatizing with perfluoroacylating reagents and analyzing by electron-capture gas chromatography and by combined gas chromatography-mass spectrometry. In experiments in vitro, p-hydroxytranylcypromine was demonstrated to inhibit monoamine oxidase, although it was weaker than TCP in this regard and was a much stronger inhibitor of MAO-A than of MAO-B.

Animals↗

PubMed1984

Brain levels of 5-hydroxytryptamine, tryptamine and 2-phenylethylamine in the rat after administration of N-cyanoethyltranylcypromine.

Brain levels of 5-hydroxytryptamine (5-HT), tryptamine (T), 2-phenylethylamine (PEA) and monoamine oxidase activity at 5, 15, 30, 60, 120 and 240 min were determined in male Sprague-Dawley rats after intraperitoneal injection of the "pro-drug" N-2-cyanoethyltranylcypromine (CE-TCP, dose 0.1 mMole/kg). Analyses of 5-HT, T and PEA were performed on an electron-capture gas chromatograph with a capillary column. Activity of MAO-A and MAO-B was measured using a radiochemical method. Results indicate substantial inhibition of MAO in rat brain after intraperitoneal administration of CE-TCP, leading to elevated levels of 5-HT, T and PEA as early as 5 min after drug administration. Increases in brain levels of the trace amines T and PEA were much greater (approximately 40 and 100 times control levels, respectively) than with 5-HT (approximately 1.8 times control level) 240 min after administration of CE-TCP.

Animals↗

PubMed1983

Some in vivo responses to a side chain monofluorinated amphetamine in the rat.

Mature male or female Sprague-Dawley rats were injected intraperitoneally with various doses (0.005, 0.027 and 0.05 mM/Kg) of (+) amphetamine sulfate or (+)-alpha-fluoromethyl-beta-phenylethylamine hydrochloride. Core (rectal) body temperatures were measured at pretreatment and 30, 60, 90, 120, 180, 240 and 300 minutes after treatment. Injection of (+)amphetamine resulted in increased body temperatures in all dose groups excepting males in the low dose (0.005 mM/kg) group after which temperatures returned to and remained at control levels. Injection of (+)alpha-fluoromethylphenylethylamine resulted in initially increased temperatures in all dose groups and at 180 minutes reduced temperatures in high dose males and in medium and high dose females. Hypothermia was not observed after treatment with (+)amphetamine. These results suggest that (+)alpha-fluoromethyl-beta-phenylethylamine has chemical properties distinct from those of (+)-amphetamine.

Amphetamines↗

PubMed1983

Stereoisomeric tetrahydro-beta-carbolines differ in their interaction with rat brain benzodiazepine receptors.

A series of (+) and (-) tetrahydro-beta-carboline-3-carboxamide stereoisomers related to the ethyl ester of beta-carboline-3-carboxylate (beta-CCE) have been tested for their ability to displace 3H-flunitrazepam from binding sites prepared from rat cerebral cortex (benzodiazepine receptors). The (+) stereoisomers of ethyl and propyl 1,2,3,4-tetrahydro-beta-carboline-3-carboxamides were the most potent inhibitors of specific 3H-flunitrazepam binding and had significantly lower IC50s than the corresponding (-) isomers. Although the IC50 values for this series of tetrahydro-beta-carboline-3-carboxamides were about 1000 fold higher than the IC50 value for beta-CCE, these compounds were as potent as the beta-carboline alkaloids harmane and harmine. The title compounds may be useful stereoisomeric probes for the characterization of subtypes of specific benzodiazepine binding sites.

Animals↗

PubMed1982

Interaction of beta-carbolines with the benzodiazepine receptor. Structure-activity relationships of amide derivatives of beta-carboline and tetrahydro-beta-carboline.

1. The inhibition of specific 3H-flunitrazepam binding to rat cortical membrane preparations (benzodiazepine receptors) by a series of amide derivatives of beta-carboline and tetrahydro-beta-carboline related to the ethyl ester of beta-carboline 3-carboxylate (beta-CCE) was measured. 2. beta-Carboline amides which are unsaturated in the C ring of the beta-carboline nucleus were the most potent inhibitors of benzodiazepine receptor binding. 3. Increasing the length of the hydrocarbon moiety in the aliphatic amide side chain beyond two carbon atoms decreased potency.

Animals↗

PubMed1972