摘要:

AbstractBW 1370U87 is a potent, reversible, selective inhibitor of rat and human brain MAO‐A with a competitive mechanism of action. The ED50of BW 1370U87 for inhibition of MAO‐A in rat brain is 8 mg/kg after oral administration, and the duration of action exceeds 7 hr. The ED80dose for inhibition of MAO‐A (20 mg/kg) elevates NE, DA, and 5‐HT levels in brains of rats without significantly potentiating the blood pressure effects of a 15 mg/kg oral dose of tyramine. This dose of tyramine, extrapolated to man, exceeds the amount that could be consumed at one time from dietary sources. No inhibition of MAO‐B has been observed with BW 1370U87 either in vitro or ex vivo. BW 1370U87 was effective in the 5‐hydroxytryptophan potentiation test over the dose range that produced MAO‐A inhibition in brain in both rats and mice, and it reduced swim stress induced immobility in the Porsolt test. The compound has positive effects on abnormal social behavior produced by early social deprivation in the rhesus monkey. BW 1370U87 had no adverse cardiovascular effects in dogs or rats. It also had no significant pharmacological effects on various isolated tissue preparations and did not cause changes in the neuronal transport or the receptor systems which mediate the antidepressant effects or side effects of the tricyclic antidepressants. An acute oral dose 100 times that which produced an 80% inhibition of brain MAO‐A exhibited no signs of toxicity. BW 137OU87 appears to be a safe reversible MAO‐A inhibitor with potential for treating depression, anxiety conditions, panic, phobias, obsessive compulsive behaviors, and borderline pers

ISSN:0272-4391    

DOI:10.1002/ddr.430250302

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractBW 1370U87 is a potent, selective inhibitor of rat and human MAO‐A with a competitive mechanism of action. Ki= 0.01 μM with either serotonin or tyramine as substrate. After preincubation of BW 1370U87 with mitochondrial MAO, full enzyme activity was restored by dialysis. Following oral administration to rats, BW 1370U87 inhibited brain MAO‐A in a dose‐dependent manner, with a duration greater than 6 hr, but less than 24 hr. No significant inhibition of MAO‐B by BW 1370U87 was observed either in vitro or ex vivo. The selectivity, reversibility, and competitive kinetics of the inhibition by BW 1370U87 may contribute to an improved safety profile with this novel MAO‐A

ISSN:0272-4391    

DOI:10.1002/ddr.430250303

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractMonoamine oxidase (MAO) inhibitors increase brain concentrations of biogenic amines and decrease concentrations of the acidic metabolites of biogenic amines. It has been suggested that the magnitude of these effects is an indicator of MAO inhibition. Oral doses of BW 1370U87, moclobemide, and brofaromine were given to rats at doses previously shown to induce brain MAO‐A inhibition by at least 80%. The effects on brain biogenic amines and their metabolites were quantified 2 and 4 hr after oral dosing using HPLC with electrochemical detection. Moclobemide and BW 1370U87 induced larger increases in 5HT, NE, and DA and larger decreases in DOPAC, 5HIAA, and HVA than did brofaromine at the doses tested. At 8 hr post‐dose the effects of BW 1370U87 on 5HT, NE, DOPAC, and HVA were still significant (P≤0.05), and the time course was similar to that seen following moclobemide and brofaromine treatment. Only BW 1370U87 increased brain concentrations of biogenic amines at a dose that does not significantly potentiate pressor effects of orally administered tyr

ISSN:0272-4391    

DOI:10.1002/ddr.430250304

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractBW 1370U87, a novel, selective, reversible monoamine oxidase‐A inhibitor, was tested in the 5‐HTP (5‐hydroxytryptophan) potentiation test in mice and rats to establish its activity following systemic administration, to determine its duration of action and to determine if its effects were reversible in vivo. The behavioral effects of a threshold dose of 5‐HTP were potentiated by BW 1370U87 in mice with ED50s of 3.4 mg/kg i.p. and 18.4 mg/kg p.o. 5‐HTP potentiation occurred in rats with an ED50 of 10.4 mg/kg p.o. BW 1370U87 (20 mg/kg) was active 9 hr, but not 16 hr following oral administration, consistent with reversible enzyme i

ISSN:0272-4391    

DOI:10.1002/ddr.430250305

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractThe reversible monoamine oxidase‐A inhibitors BW 1370U87, BW 616U76, brofaromine, and moclobemide, and the irreversible nonselective monoamine oxidase inhibitor phenelzine were compared for potentiation of the pressor response to oral tyramine. Conscious rats were pretreated with doses of the monoamine oxidase inhibitors sufficient to produce 80% inhibition of brain monoamine oxidase, and then were challenged with orally administered tyramine. Blood pressure was monitored prior to and after tyramine, and peak pressor responses were compared. At a dose of 15 mg/kg tyramine, the pressor response of BW 1370U87 was statistically similar to the vehicle control response. BW 616U76, brofaromine, and moclobemide elicited mild tyramine pressor effects, whereas phenelzine resulted in a marked elevation of blood pressure. Higher doses of tyramine elicited blood pressure elevations from all of the monoamine oxidase inhibitor

ISSN:0272-4391    

DOI:10.1002/ddr.430250306

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractBW 1370U87 is a potent, selective inhibitor of rat and human brain MAO‐A. The plasma concentrations of BW 1370U87 and its metabolites were determined in rat, dog, and man. After an oral dose, BW 1370U87 undergoes extensive first‐pass metabolism in all species studied. The 1‐(1,2, dihydroxyethyl) metabolite, BW 1003U88, was a major metabolite in rat, dog, and human plasma. The 1‐(1‐hydroxyethyl) metabolite, BW 183U88, was a major metabolite in dog plasma, whereas it was present in much lower concentrations in the rat and man. Both BW 1003U88 and BW 183U88 are active MAO‐A inhibitors although not as active as the parent compound. The inactive 1‐(2‐acetic acid) metabolite, BW 1552U88, was a major metabolite in rat plasma but a minor metabolite in the dog. Plasma concentration versus time profiles in both rat and man suggest that the metabolites undergo enterohepatic recycling. Although plasma concentrations of BW 1370U87 were relatively low compared to the metabolites, the concentrations detected in rat and man after a 50 mg/kg or 400 mg oral dose, respectively, exceeded the IC50value measured in rat and human brain. Furthermore, the time course of MAO‐A inhibition appears to follow the plasma concentration versus time profile of BW 1370U87 in the rat. Preliminary experiments in rats indicate that BW 1370U87 and its metabolites distribute into brain

ISSN:0272-4391    

DOI:10.1002/ddr.430250307

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractWe employed broken cell liver preparations in order to investigate potential species‐specific differences in the metabolism of BW 1370U87, a new selective and reversible MAO‐A inhibitor. The drug metabolizing capacity of crude liver homogenates from rat, dog, cat, monkey, and man was assessed based on the utilization of BW 1370U87 and the appearance of suspected metabolites. When incubated with liver homogenates (37° C) in the presence of a cofactor preparation designed to generate TPNH, BW 1370U87 (1 or 10 μM) was metabolized in a species and time dependent manner. The rate of disappearence of BW 1370U87 was more rapid in dog and cat preparations than those of rat, monkey and man. The appearance of metabolites coincided with the disappearance of BW 1370U87. Three metabolites, identified and synthesized as BW 183U88, BW 380U88, and BW 330U88 appeared in all five species. These metabolites were also found to be selective MAO‐A inhibitors both in vitro and ex vivo and may contribute to the overall activity exhibited by the parent m

ISSN:0272-4391    

DOI:10.1002/ddr.430250308

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractThe effects of i.v. administration of the antidepressant compound nefazodone were assessed on the firing rates of spontaneously active noradrenergic neurons in the locus coeruleus (LC), serotonergic neurons in the dorsal raphe (DR), and dopaminergic neurons in the substantia nigra (SN) of chloral hydrate anesthetized male albino adult rats, utilizing extracellular single‐unit recording methods. Nefazodone, tested in doses of 0.1–10.0 mg/kg, had variable effects on LC neurons, but the predominant effect was a mild excitation of firing (ED25= 1.953 mg/kg). This may in part be caused by the 5‐HT2antagonist properties of the compound, since ritanserin also produced a mild excitation of LC neurons. By comparison, desipramine very reliably inhibited LC neurons (ED50= 0.333 mg/kg, i.v.). For DR neurons, i.v. nefazodone (0.1–3.2 mg/kg) produced variable effects, with inhibition being the most common (63% of cases tested). The ED25for inhibition was 1.230 mg/kg, and in no case was inhibition of 50% or greater observed. By comparison, clomipramine very reliably inhibited DR neurons (ED50= 0.501 mg/kg, i.v.). For SN neurons, the effects of i.v. nefazodone were also variable, with no consistent effects observed. These results indicate that acute nefazodone produces relatively weak effects on monoaminergic neuronal impulse flow in anesthetized rats, and suggest that major modifications of monoaminergic neuronal impulse flow probably do not play an important role in any neuroadaptive changes that may contribute to the clinical antidepressant actions of nef

ISSN:0272-4391    

DOI:10.1002/ddr.430250309

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430250301

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY