ABSTRACT-The present study characterizes the neurochemical profile of the newly synthesized compound 5-{3-[((2S)-1,4-benzodioxan-2-ylmethyl)amino]propoxy}-1,3-benzodioxole HC1 (MKC-242). In in vitro experiments, MKC-242 had high affinity for serotonin,A (5-HTIA) receptors (K;: 0.35 nM) and moderate affinity for a,-adrenoceptors (K,: 21 nM), whereas it had no appreciable affinity for any other neurotransmitter recognition sites studied and 5-HT transporter. MKC-242 (0.3-3.0 mg/kg, s.c.; 1-10 mg/kg, p.o.) caused presynaptic 5-HT,A-receptor-mediated responses (decreases in 5-HT turnover and 5-HT release) and postsynaptic 5-HT,A-receptor-mediated responses (hypothermia, an increase in serum corticosterone level and 5-HT,A behavioral syndrome). The effects of MKC-242 on decarboxylase inhibitor-induced 5-hydroxytryptophan accumulation and rectal temperature were blocked by the 5-HT,A-receptor antagonist N-tert-butyl-3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenylpropanamide.The comparative studies on the in vivo responses induced by MKC-242 and the 5-HT,A-receptor full agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) showed that MKC-242 and 8-OH-DPAT had similar efficacy at presynaptic 5-HT,A receptors, whereas the former had less efficacy than the latter at postsynaptic 5-HT,A receptors. Furthermore, MKC-242 partially inhibited forskolin-stimulated adenylate cyclase activity in hippocampal membranes. These findings suggest that MKC-242 acts as a full and partial agonist at pre-and postsynaptic 5-HT,A receptors, respectively, in the central nervous system.
TANAKA, M.; WATANABE, K.; TAKAMATSU, Y.; TOBE, A.; Yakugaku Zasshi 124 (2004) 3, 99-111; Sales Marketing Div., Mitsubishi Pharma Corp., Chuo, Osaka 541, Japan; Japan., Abstr. Eng.) -Lindner 28-239
Increasing data suggest that oxygen free radical species play detrimental roles in ischemic diseases. A free radical scavenger capable of inhibiting oxidative injury is expected to become a new drug for the treatment of ischemic diseases such as cerebral ischemia. Edaravon (3-methyl-1-phenyl-2-pyrazolin-5-one), which has been developed as an neuroprotective agent for more than 15 years since its discovery, is approved for the treatment of acute cerebral infarction. In this paper, the pharmacologic characteristics and clinical eŠects of edaravone are reviewed. In early stage of investigation, edaravone was found to have promising activities as an antioxidative radical scavenger, quenching hydroxyl radical (・OH) and inhibiting both・OH-dependent and・OH-independent lipid peroxidation. Edaravone showed inhibitory eŠects on both water-soluble and lipid-soluble peroxyl radical-induced peroxidation systems, which are diŠerent from the inhibitory eŠects of vitamins C and E in each system, respectively. Oxidative injury to cultured endothelial cells caused by arachidonate (AA) peroxides is prevented in the existence of edaravone. To clarify the characteristics of this free radical scavenger, further investigation was carried out. Edaravone ameliorated exacerbation of cortical edema induced by a focal ischemia-reperfusion model in rats, suggesting inhibitory eŠects on oxidative injury to the blood-brain barrier (BBB). Additionally, edaravone also prevented rat cortical edema caused by intracortical AA infusion in which free radical production and subsequent oxidative injury to the BBB are involved. With advances in in vivo measurement technology of oxygen radicals, edaravone was shown to inhibit postischemic increases in・OH production and tissue injury in the penumbral or recirculated area in rat cerebral ischemia models. In clinical studies, edaravone improved the core neurologic deˆcits, activities of daily living, and functional outcome of stroke patients. Furthermore, a study using proton magnetic resonance spectroscopic techniques showed that edaravone preserved N-acetyl-aspartate in stroke patients, a promising neuronal marker in the brain. Further investigation is essential for a better understanding of free radical-mediated cerebral injury during ischemia followed by recirculation. We hope that edaravone represents a promising neuroprotectant for drug therapy in acute cerebral ischemia.
BackgroundDabigatran is a direct thrombin inhibitor used to decrease the risk of ischemic stroke in patients with non-valvular atrial fibrillation (NVAF). Its prodrug, dabigatran etexilate (DE) is often co-administrated with a proton pump inhibitor (PPI) because of its adverse effects on the gastrointestinal tract. Drug-drug interactions between DE and PPIs in daily clinical practice have not been fully elucidated.MethodsChanges in blood dabigatran concentration (DC) were investigated using the dilute thrombin time test in a randomized, open-label, two-period crossover study including 34 Japanese patients with NVAF receiving dabigatran therapy with or without PPI.ResultsThe average trough DC was significantly higher without PPI than with PPI (83 ± 42.3 vs. 55.5 ± 24.6 ng/mL, respectively; P < 0.001). Similarly, the average peak DC was significantly higher without PPI than with PPI (184.1 ± 107.7 vs. 124 ± 59.2 ng/mL, respectively; P = 0.0029). The average ratio of DC change at the trough and peak levels did not differ significantly among the three PPI types.ConclusionsPPI administration significantly decreased the trough and peak DCs in patients with NVAF. Therefore, when prescribing PPIs for patients with NVAF in a clinical setting, the possibility that the bioavailability of dabigatran may decrease should be considered.
A series of substituted (omega- aminoalkoxy )stilbene derivatives has been synthesized and screened for anticonvulsant activity. The effect of structural modification of these molecules on the activities has been systematically examined. Potent anticonvulsant activity was displayed by 2-[4-(4-methyl-1 piperazinyl)butoxy]stilbene (20) and some 2-[4-(3-alkoxy-1-piperidino)butoxy]stilbene derivatives (21, 37, 38, and 40), as determined by maximal electroshock seizure (MES) and pentylenetetrazol-induced convulsion tests in mice. Compound 21 exhibited more potent anti-MES activity than diphenylhydantoin and carbamazepine in further pharmacological tests in rats, and its therapeutic index was superior to those of two antiepileptic drugs.
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