Home About us Contact
|
Home About us Contact | ||
|
|
||
MAO-B Inhibitors (mao-b + inhibitor)
Selected AbstractsMonoamine oxidase A rather than monoamine oxidase B inhibition increases nicotine reinforcement in ratsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2006Karine Guillem Abstract Although nicotine is considered to be responsible for the addictive properties of tobacco, growing evidence underlines the importance of non-nicotine components in smoking reinforcement. It has been shown that tobacco smoke contains monoamine oxidase (MAO) A and B inhibitors and decreases MAO-A and MAO-B activity in smokers. Here, we investigated the effects of clorgyline hydrochloride (irreversible MAO-A inhibitor; 2 mg/kg/day), selegiline (irreversible MAO-B inhibitor; 4 mg/kg) and the beta-carboline norharmane hydrochloride (reversible MAO-B inhibitor; 5 mg/kg/day) treatments on nicotine self-administration (30 µg/kg/infusion, free base) in rats. Independent of the responsiveness to novelty and locomotor activity stimulation, only clorgyline hydrochloride treatment increased the intake of nicotine in a fixed-ratio schedule (FR5) of reinforcement. When a progressive-ratio schedule was implemented, both clorgyline hydrochloride and norharmane hydrochloride treatments potentiated the reinforcing effects of nicotine, whereas selegiline had no effect. Taken together, these results indicate that MAO-A inhibition interacts with nicotine to enhance its rewarding effects in rats and suggest that other compounds present in tobacco, such as beta-carboline, may also play an important role in sustaining smoking behavior in humans. [source] Selegiline, an MAO-B inhibitor, attenuates airway smooth muscle contraction in the rat tracheaJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2004Maki Yoshimura Selegiline is widely used for Parkinson's disease and sometimes for Alzheimer's disease. It is reported to affect intracellular Ca2+ concentration. Since intracellular Ca2+ is partly regulated by phosphatidylinositol (PI) response and is important for smooth muscle contraction, selegiline may affect airway smooth muscle tension. We examined the effects of selegiline on acetylcholine (ACh)- and KCl-induced contractile and PI responses in rat trachea. The trachea was cut into 3-mm-wide ring segments or 1-mm-wide slices. ACh (3 ,M, 50% effective dose) or KCl (40mM) was added, and ring relaxation was induced by the addition of selegiline. Tracheal slices were incubated with [3H]myo -inositol and 3 ,M ACh in the presence of selegiline, and [3H]inositol monophosphate (IP1) was measured. Selegiline dose-dependently attenuated ACh- and KCl-induced tracheal ring contractions. Fifty-percent inhibitory doses (ID50) of selegiline against ACh- and KCl-induced contraction were 120±30 ,M and 80±20 ,M, respectively. Basal and ACh-induced IP1 accumulation were 2.20±0.20 Bq and 7.88±0.23 Bq, respectively, and selegiline at a dose of 1000 ,M attenuated ACh-induced IP1 accumulation (5.44±0.30 Bq). These results suggest that selegiline inhibits contractile responses through the inhibition of voltage-operated Ca2+ channels and the PI response. [source] Lipophilicity Plays a Major Role in Modulating the Inhibition of Monoamine Oxidase B by 7-Substituted CoumarinsCHEMISTRY & BIODIVERSITY, Issue 2 2006Angelo Carotti Abstract A series of coumarin derivatives (1,22), bearing at the 7-position ether, ketone, ester, carbamate, or amide functions of varying size and lipophilicity, were synthesized and investigated for their in vitro monoamine oxidase-A and -B (MAO-A and -B) inhibitory activities. Most of the compounds acted preferentially as MAO-B inhibitors, with IC50 values in the micromolar to low-nanomolar range. A structure,activity-relationship (SAR) study highlighted lipophilicity as an important property modulating the MAO-B inhibition potency of 7-substituted coumarins, as shown by a linear correlation (n=20, r2=0.72) between pIC50 and calculated log P values. The stability of ester-containing coumarin derivatives in rat plasma provided information on factors that either favor (lipophilicity) or decrease (steric hindrance) esterase-catalyzed hydrolysis. Two compounds (14 and 22) were selected to investigate how lipophilicity and enzymatic stability may affect in vivo MAO activities, as assayed ex vivo in rat. The most-potent and -selective MAO-B inhibitor 22 (=7-[(3,4-difluorobenzyl)oxy]-3,4-dimethyl-1-benzopyran-2(2H)-one) within the examined series significantly inhibited (>60%) ex vivo rat-liver and striatal MAO-B activities 1,h after intraperitoneal administration of high doses (100 and 300,,mol kg,1), revealing its ability to cross the blood,brain barrier. At the same doses, liver and striatum MAO-A was less inhibited in vivo, somehow reflecting MAO-B selectivity, as assessed in vitro. In contrast, the metabolically less stable derivative 14, bearing an isopropyl ester in the lateral chain, had a weak effect on hepatic MAO-B activity in vivo, and none on striatal MAO-B, but, surprisingly, displayed inhibitory effects on MAO-A in both peripheral and brain tissues. [source] Selective MAO-B inhibitors have low potential for the tyramine effectMOVEMENT DISORDERS, Issue 1 2010Stuart H. Isaacson MD No abstract is available for this article. [source] Neuroprotection trials in Parkinson's disease: Systematic review,,MOVEMENT DISORDERS, Issue 5 2009Robert G. Hart MD Abstract Treatments to slow the progression are a major unmet need in Parkinson's disease. Detailed assessment of randomized trials testing putative neuroprotective drugs was undertaken to inform the design, reporting, and interpretation of future studies. This study is a systematic review of trials testing neuroprotective drugs. Data were extracted independently by two coauthors. Fifteen completed, published trials involving 4,087 participants tested 13 different drugs in 18 double-blind comparisons with placebo. Seven comparisons involving 2,000 subjects assessed MAO-B inhibitors. The primary outcome was change in the Unified Parkinson's Disease Rating Scale score in eight trials and time to need for dopaminergic therapy in seven. Mean participant age was 62 years, 35% were women, the interval from diagnosis to entry averaged 11 months, and the number of participants averaged 272 (largest = 806). Follow-up averaged <16 months in all but two trials. Detailed randomization methods and success of double-blinding were reported in 20% and 13%, respectively. Based on the investigators' conclusions, six trials were interpreted as consistent with a neuroprotective effect, three as negative, and five as either confounded or not meeting criteria for futility. Neuroprotection trials have involved relatively uniform groups of participants early in the clinical disease course, with outcomes weighted heavily toward motor deterioration. Future trials should include participants with wider ranges of disease stages and assess broader neurological outcomes. © 2008 Movement Disorder Society [source] MAO-B inhibitors for the treatment of Parkinson's diseaseMOVEMENT DISORDERS, Issue S4 2002Article first published online: 29 JUL 200 [source] Lipophilicity Plays a Major Role in Modulating the Inhibition of Monoamine Oxidase B by 7-Substituted CoumarinsCHEMISTRY & BIODIVERSITY, Issue 2 2006Angelo Carotti Abstract A series of coumarin derivatives (1,22), bearing at the 7-position ether, ketone, ester, carbamate, or amide functions of varying size and lipophilicity, were synthesized and investigated for their in vitro monoamine oxidase-A and -B (MAO-A and -B) inhibitory activities. Most of the compounds acted preferentially as MAO-B inhibitors, with IC50 values in the micromolar to low-nanomolar range. A structure,activity-relationship (SAR) study highlighted lipophilicity as an important property modulating the MAO-B inhibition potency of 7-substituted coumarins, as shown by a linear correlation (n=20, r2=0.72) between pIC50 and calculated log P values. The stability of ester-containing coumarin derivatives in rat plasma provided information on factors that either favor (lipophilicity) or decrease (steric hindrance) esterase-catalyzed hydrolysis. Two compounds (14 and 22) were selected to investigate how lipophilicity and enzymatic stability may affect in vivo MAO activities, as assayed ex vivo in rat. The most-potent and -selective MAO-B inhibitor 22 (=7-[(3,4-difluorobenzyl)oxy]-3,4-dimethyl-1-benzopyran-2(2H)-one) within the examined series significantly inhibited (>60%) ex vivo rat-liver and striatal MAO-B activities 1,h after intraperitoneal administration of high doses (100 and 300,,mol kg,1), revealing its ability to cross the blood,brain barrier. At the same doses, liver and striatum MAO-A was less inhibited in vivo, somehow reflecting MAO-B selectivity, as assessed in vitro. In contrast, the metabolically less stable derivative 14, bearing an isopropyl ester in the lateral chain, had a weak effect on hepatic MAO-B activity in vivo, and none on striatal MAO-B, but, surprisingly, displayed inhibitory effects on MAO-A in both peripheral and brain tissues. [source] | ||||||||||