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PubMed2006

Modulation of nociceptive dural input to the trigeminal nucleus caudalis via activation of the orexin 1 receptor in the rat.

Migraine pathophysiology is thought to involve the trigeminal innervation of the dura mater and intracranial blood vessels. Electrical stimulation of dural blood vessels is painful in humans and causes activation of neurons in the caudal-most portion of the trigeminal nucleus in experimental animals. The hypothalamic neuropeptides orexin A and B are selectively synthesized in the lateral and posterior hypothalamus, and recent findings have implicated their involvement in nociceptive processing. To evaluate the potential for orexin receptor modulation of trigeminovascular nociceptive afferents, we examined the effects of intravenous orexin A and B on responses of neurons in the trigeminal nucleus caudalis. To dissect the receptor pharmacology of responses to stimulation we utilized the novel orexin 1 receptor (OX(1)R) antagonist N-(2-methyl-6-benzoxazolyl)-N''-1,5-naphthyridin-4-yl urea (SB-334867). Orexin A 30 microg/kg (F(1.9,9.8) = 21.93, P < 0.001) and 50 microg/kg (F(3.2,16.4) = 3.28, P < 0.045) inhibited the A-fibre responses to dural electrical stimulation over 60 min. Maximum inhibition was achieved at 25 min for both 30 microg/kg (t(5) = 19.83, n = 6, P < 0.001) and 50 microg/kg (t(5) = 7.74, n = 6, P < 0.001). The response with orexin A 30 microg/kg was reversed by pretreatment with the OX(1)R antagonist SB-334867 (F(3.5,17.5) = 0.49, P = 0.73), which had no effect when given alone. Orexin B and control vehicle administration had no significant effect on trigeminal neuronal firing. The current study demonstrates that orexin A is able to inhibit A-fibre responses to dural electrical stimulation via activation of the OX(1)R.

Action Potentials↗
PubMed1993

The pharmacology of RS-15385-197, a potent and selective alpha 2-adrenoceptor antagonist.

1. RS-15385-197 ((8aR, 12aS, 13aS)-5,8,8a,9,10,11,12,12a,13,13a-decahydro- 3-methoxy-12-(methylsulphonyl)-6H-isoquino [2,1-g][1,6]-naphthyridine) was evaluated in a series of in vitro and in vivo tests as an antagonist at alpha 2-adrenoceptors. 2. RS-15385-197 had a pKi of 9.45 for alpha 2-adrenoceptors in the rat cortex (pA2 in the guinea-pig ileum of 9.72), whereas the 8aS, 12aR, 13aR enantiomer, RS-15385-198, had a pKi of only 6.32 (pA2 6.47) indicating a high degree of stereoselectivity. The racemate RS-15385-196 had a pKi of 9.18. 3. RS-15385-197 showed unprecedented alpha 2 vs. alpha 1 adrenoceptor selectivity in vitro. In the rat cortex, RS-15385-197 had a pKi of 9.45 in displacing [3H]-yohimbine and 5.29 in displacing [3H]-prazosin (alpha 2/alpha 1 selectivity ratio in binding experiments > 14000). The compound had a pA2 of 9.72 as a competitive antagonist of the inhibitory effects of UK-14,304 in transmurally-stimulated guinea-pig ileum and 10.0 against BHT-920-induced contractions in dog saphenous vein (DSV); this latter value was unaltered by phenoxybenzamine. An apparent pKB of 5.9 was obtained against cirazoline-induced contractions in DSV, whilst a pA2 of 6.05 was obtained against phenylephrine-induced contractions in the rabbit aorta (alpha 2/alpha 1 selectivity ratio in functional experiments > 4000). 4. RS-15385-197 was highly selective for alpha 2-adrenoceptors over other receptors: the compound showed low affinity for 5-HT1A (pKi 6.50) and 5-HT1D (pKi 7.00) receptor subtypes, and even lower affinity (pKi < or = 5) for other 5-HT receptor subtypes, dopamine receptors, muscarinic cholinoceptors, beta-adrenoceptors and dihydropyridine binding sites. RS-15385-197 was devoid of affinity for the non-adrenoceptor imidazoline binding site, labelled by [3H]-idazoxan, which provides further evidence that these sites are not related to alpha 2-adrenoceptors. In the DSV, contractile responses to 5-hydroxytryptamine (5-HT) were unaffected by a concentration of 1 microM RS-15385-197. 5. RS-15385-197 was non-selective for the alpha 2A- and alpha 2B-adrenoceptor subtypes in that the pKi for the alpha 2A-adrenoceptor in human platelets was 9.90 and the pKi for the alpha 2B-adrenoceptor in rat neonate lung was 9.70. However, RS-15385-197 showed lower affinity for the alpha 2-adrenoceptor subtype in hamster adipocytes (pKi 8.38). 6. In anaesthetized rats, RS-15385-197 was a potent antagonist of the mydriasis response induced by UK-14,304 or clonidine (AD50 5 and 7 microg kg-1, i.v., respectively; 96 microg kg-1, p.o.) and of UK-14,304-induced pressor responses in pithed rats (AD50 7 microg kg-1, i.v.); the compound therefore is both centrally and orally active. Even at a high dose (10 mg kg-1, i.v.), RS-15385-197 did not antagonize pressor responses to cirazoline in pithed rats, indicating that the selectivity for alpha2 vs. alpha1-adrenoceptors was maintained in vivo.8 RS-15385-197 is therefore a very potent, selective, competitive alpha2-adrenoceptor antagonist, both in vitro and in vivo, is orally active and readily penetrates the brain. It will thus be a powerful pharmacological tool for exploring the various physiological roles of alpha2-adrenoceptors.

Administration, Oral↗
PubMed2002

Peripheral activity of a new NK1 receptor antagonist TAK-637 in the gastrointestinal tract.

Pathways controlling gastrointestinal function involve the activation of neurokinin NK1 receptors by substance P (SP) under normal and pathological conditions. Our aim was to pharmacologically characterize the effect of a nonpeptide NK1 receptor antagonist TAK-637 [(aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g] [1,7]naphthyridine-6,13-dione] and determine key mechanisms of TAK-637 action in the gastrointestinal tract. Experiments were performed using intestinal preparations isolated from the guinea pig. The selective agonists of NK1 receptors, [Sar9,Met(O2)11]-SP and GR 73632 [H2N-(CH2)4-CO-Phe-Phe-Pro-NMe-Leu-Met-NH2], induced contractions in colonic longitudinal muscle pretreated with atropine. TAK-637 (1-100 nM) caused a rightward shift of the concentration-response curves showing nanomolar affinity against [Sar9,Met(O2)11]-SP (Kb = 4.7 nM) and GR 73632 (K(b) = 1.8 nM). This antagonist effect remained unchanged by tetrodotoxin. Furthermore, neither the contractions of colonic circular muscle induced by selective activation of NK2 receptors by GR 64349 (Lys-Asp-Ser-Phe-Val-Gly-R-gamma-lactam-Leu-Met-NH2) nor the responses of taenia coli induced by the selective NK3 receptor agonist senktide were affected by TAK-637 (100 nM). Studies of electrically induced neurogenic contractions showed that TAK-637 had no effect on cholinergic responses to single-pulse (0.5 ms) stimulation or stimulation with increasing frequency (1-16 Hz, 0.5 ms, 5-s train duration). In contrast, TAK-637 significantly reduced nonadrenergic, noncholinergic contractions of colonic longitudinal muscle evoked at frequencies of 8 to 16 Hz and prevented the development of capsaicin-induced contractions in isolated segments of terminal ileum. Our results indicate that TAK-637 is a selective antagonist of smooth muscle NK(1) receptors that activate intestinal muscle contraction. Additionally TAK-637 inhibits neuronal NK1 receptors involved in the "local" motor response to stimulation of capsaicin-sensitive primary afferents.

Animals↗
PubMed2002

Effects of tachykinin NK1 receptor antagonists on the viscerosensory response caused by colorectal distention in rabbits.

Irritable bowel syndrome (IBS) is a common disorder mainly characterized by altered bowel habits and visceral pain. In this study, we investigated the role of tachykinin NK1 receptors in the visceral pain response (abdominal muscle contraction) caused by colorectal distention in rabbits previously subjected to colonic irritation, using the selective tachykinin NK1 receptor antagonists TAK-637 [(aR,9R)-7-[3,5-Bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4] diazocino[2,1-g][1,7]naphthyridine-6,13-dione] and (+/-)-CP-99,994 (+/-)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine. Intracolorectal administration of 0.8% acetic acid solution enhanced the nociceptive response to colorectal distention, producing a significant increase in the number of abdominal muscle contractions. Under these conditions, intraduodenal TAK-637 (0.1-3 mg/kg) dose dependently decreased the number of distention-induced abdominal contractions, and a significant inhibitory effect was observed with doses of 0.3 to 3 mg/kg. Another tachykinin NK1 antagonist, (+/-)-CP-99,994, also reduced the number of abdominal contractions. In contrast, the enantiomer of TAK-637 (which has very weak tachykinin NK1 receptor antagonistic activity), trimebutine maleate, ondansetron, and atropine sulfate did not inhibit the abdominal response. The main metabolite of TAK-637, which has more potent tachykinin NK1 receptor antagonistic activity but permeates the central nervous system less well than TAK-637, produced less inhibition of the viscerosensory response. When given intrathecally, TAK-637 and (+/-)-CP-99,994 markedly reduced the number of abdominal contractions. These results suggest that tachykinin NK1 receptors play an important role in mediating visceral pain and that TAK-637 inhibits the viscerosensory response to colorectal distention by antagonizing tachykinin NK1 receptors, mainly in the spinal cord. They also suggest that TAK-637 may be useful in treating functional bowel disorders such as IBS.

Acetates↗
PubMed2006

Targeting of hematin by the antimalarial pyronaridine.

Pyronaridine, 2-methoxy-7-chloro-10[3',5'-bis(pyrrolidinyl-1-methyl-)4'hydroxyphenyl]aminobenzyl-(b)-1,5-naphthyridine, a new Mannich base schizontocide originally developed in China and structurally related to the aminoacridine drug quinacrine, is currently undergoing clinical testing. We now show that pyronaridine targets hematin, as demonstrated by its ability to inhibit in vitro beta-hematin formation (at a concentration equal to that of chloroquine), to form a complex with hematin with a stoichiometry of 1:2, to enhance hematin-induced red blood cell lysis (but at 1/100 of the chloroquine concentration), and to inhibit glutathione-dependent degradation of hematin. Our observations that pyronaridine exerted this mechanism of action in situ, based on growth studies of Plasmodium falciparum K1 in culture showing antagonism of pyronaridine in combination with antimalarials (chloroquine, mefloquine, and quinine) that inhibit beta-hematin formation, were equivocal.

Animals↗
PubMed1978

PC-904, a new semisynthetic penicillin.

Sodium 6{d(-)-alpha(4-hydroxyl-1,5 naphthyridine-3-carboxamido)phenylacetamido} penicillanate (PC-904) is a new semisynthetic penicillin with broad-spectrum activity against gram-positive cocci and gram-negative bacilli. At a concentration of 1.56 mug/ml, it inhibited 100% of isolates of Proteus mirabilis, 89% of Pseudomonas aeruginosa, 67% of Escherichia coli, and 45% of Enterobacter spp. At a concentration of 12.5 mug/ml, it inhibited 75% of Klebsiella spp. and 67% of Serratia marcescens. PC-904 failed to inhibit the growth of gram-negative bacilli when large inocula were used. Some differences were noted when organisms were tested in different media or at different hydrogen ion concentrations. It is more active than mezlocillin, azlocillin, ticarcillin, carbenicillin, and amoxicillin against E. coli, Klebsiella spp., and P. aeruginosa.

Ampicillin↗
PubMed1983

In vitro antibacterial properties of AT-2266, a new pyridonecarboxylic acid.

AT-2266, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3 -carboxylic acid, is a new pyridonecarboxylic acid derivative with broad and potent antibacterial activity. It inhibited some gram-positive bacteria, such as staphylococci and Bacillus subtilis, and most gram-negative bacteria, including Serratia marcescens, Pseudomonas aeruginosa, Haemophilus influenzae, and Campylobacter jejuni, at concentrations of 0.1 to 0.78 microgram/ml, and most gram-positive bacteria, glucose-nonfermenters, and Mycoplasma pneumoniae at concentrations of 1.56 to 12.5 micrograms/ml. Most of the clinical isolates tested were as susceptible to AT-2266 as were laboratory strains. The antibacterial potency of AT-2266 was higher than those of pipemidic acid and nalidixic acid and similar to that of norfloxacin. AT-2266 was not cross-resistant with antibiotics and inhibited most highly nalidixic acid-resistant bacteria at concentrations of 1.56 to 3.13 micrograms/ml. Its activity was barely affected by the addition of horse serum or sodium cholate but weakened by lowering the medium pH or increasing the inoculum size. AT-2266 was bactericidal at concentrations near its minimal inhibitory concentrations. Frequencies of mutants resistant to 10 micrograms of AT-2266 per ml were lower than 4.0 x 10(-9).

Anti-Bacterial Agents↗
PubMed1983

Activity of AT-2266 compared with those of norfloxacin, pipemidic acid, nalidixic acid, and gentamicin against various experimental infections in mice.

AT-2266 (1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1, 8-naphthyridine-3-carboxylic acid) showed marked activity in vivo when administered orally to mice bearing systemic, pulmonary, dermal, or urinary tract infections due to variety of organisms. The activity of AT-2266 was uniformly higher than those of norfloxacin, pipemidic acid, and nalidixic acid against all of the infections. The activity of AT-2266 administered orally was almost comparable to that of gentamicin administered subcutaneously against urinary tract infections due to gram-negative organisms but was generally lower against other infections. AT-2266 exhibited significant activity against infections due to gentamicin-resistant and nalidixic acid-resistant organisms.

Animals↗
PubMed1983

Pharmacokinetics of AT-2266 administered orally to mice, rats, dogs, and monkeys.

The pharmacokinetics of AT-2266 (1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine- 3-carboxylic acid) were studied in various experimental animals and compared in a number of aspects with those of norfloxacin. Both agents were administered orally. The mean peak plasma levels of AT-2266 in mice, rats, and dogs (given a single dose of 50 mg/kg for mice and rats and 25 mg/kg for dogs) were 2.39, 1.63, and 5.00 mug/ml, respectively, with elimination half-lives of 2.24, 2.81, and 5.76 h. The respective mean plasma levels of norfloxacin at similar dosages were 0.510, 0.410, and 0.700 mug/ml; elimination half-lives were 1.40, 2.35, and 6.06 h. In dogs repeatedly dosed with 25 mg of AT-2266 per kg every 12 h, the mean peak plasma levels after the third and fifth doses were about 1.4 times those after the first dose. The binding rates of AT-2266 and norfloxacin to plasma of mice, rats, and dogs and to human serum ranged from 27.6 to 40.2% and 39.8 to 44.2%, respectively. In rats receiving a single dose of 50 mg/kg, the respective mean peak levels of AT-2266 in plasma, lung, muscle, and kidney were 2.47, 4.60, 5.35, and 33.9 mug/ml or g, whereas those of norfloxacin were 0.234, 0.390, 0.272, and 2.05 mug/ml or g. AT-2266 was widely distributed in tissues of dogs and monkeys after repeated dosage. The respective 24-h recoveries of AT-2266 from urine of mice, rats, and dogs after single doses of 50, 50, and 25 mg/kg were 56.6, 40.5, and 64.1%, and recoveries of norfloxacin at these doses were 4.40, 2.91, and 5.34%. The respective 24-h recoveries of AT-2266 from bile and feces of rats given a single dose of 50 mg/kg were 2.47 and 52.7%. Bioautography of plasma and urine indicated that AT-2266 was metabolized to but a slight degree. The results indicate that AT-2266 is better than norfloxacin in oral absorption and similar to the latter in stability to metabolic inactivation.

Administration, Oral↗
PubMed1983

In vitro and in vivo antibacterial activity of AT-2266.

AT-2266 [1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carbo xylic acid] showed a broad spectrum of antibacterial activity against gram-positive and gram-negative microorganisms, including Pseudomonas aeruginosa. The in vitro antibacterial activity of AT-2266 was in general comparable to that of norfloxacin, but much higher than that of pipemidic or nalidixic acid. The 90% minimal inhibitory concentrations (MIC90s) of AT-2266 for P. aeruginosa resistant to gentamicin (MIC range, 25 to greater than 200 microgram/ml) and Enterobacteriaceae resistant to nalidixic acid (25 to greater than 1,600 micrograms/ml) were 3.13 and 12.5 micrograms/ml, respectively. The to nalidixic acid (25 to 1,600 micrograms/ml) were 3.13 and 12.5 micrograms/ml, respectively. The MICs of AT-2266 were only slightly affected by the addition of horse serum or sodium cholate, by the pH of the medium, and by inoculum size. AT-2266 was sodium cholate, by the pH of the medium, and by inoculum size. AT-2266 was bactericidal at concentrations near its MIC value. The 50% effective doses of AT-2266 after oral administration against systemic infections in mice were about 1/2 those of norfloxacin, about 1/10 those of pipemidic acid, and between 1/20 and 1/40 those of nalidixic acid.

Animals↗
PubMed1988

Comparative in vitro activity of a new fluorinated 4-quinolone, T-3262 (A-60969).

The in vitro activity of a new quinolone, T-3262 [A-60969; DL-7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1-, 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid monohydrate], was compared with those of ciprofloxacin, ofloxacin, ceftazidime, imipenem, and gentamicin. T-3262 inhibited 90% of isolates of the family Enterobacteriaceae at a concentration of less than or equal to 0.25 micrograms/ml. It was two to four times more active than ofloxacin and similarly or slightly less active than ciprofloxacin. Ninety percent of isolates of Pseudomonas aeruginosa were inhibited at 0.5 micrograms/ml. It was 4- to 8-fold more active than ciprofloxacin and 8- to 16-fold more active than ofloxacin against Pseudomonas cepacia and Pseudomonas maltophilia, which were resistant to imipenem and gentamicin. Most Haemophilus influenzae, Neisseria gonorrhoeae, and Branhamella catarrhalis isolates were inhibited at concentrations of less than or equal to 0.008 micrograms/ml. The MIC for 90% of the Staphylococcus aureus isolates, including methicillin-resistant S. aureus, was 0.12 micrograms/ml; that for Staphylococcus epidermidis was 0.5 micrograms/ml, as was that for Enterococcus faecalis. It inhibited 90% of Bacteroides fragilis isolates at 2 micrograms/ml, considerably more active than ciprofloxacin and ofloxacin. The frequency of spontaneous point mutational resistance was less than 10(-10) for members of the family Enterobacteriaceae and Pseudomonas spp. Resistant strains could be selected by repeated subculture. Similar to other quinolones, its activity could be affected by culture conditions. T-3262 showed a postantibiotic suppressive effect on Escherichia coli, P. aeruginosa, and S. aureus.

Anti-Bacterial Agents↗
PubMed1976

PC-904, a novel broad-spectrum semisynthetic penicillin with marked antipseudomonal activity: microbiological evaluation.

PC-904, sodium 6-{d(-)-alpha-(4-hydroxy-1,5-naphthyridine-3-carboxamido) phenylacetamido}-penicillanate, is a novel semisynthetic penicillin derivative that possesses a broad spectrum of in vitro and in vivo antibacterial activities. In low concentrations, PC-904 inhibits growth against large proportions of the gram-positive and gram-negative organisms susceptible to carbenicillin and gentamicin. In addition, PC-904 is several times more potent than carbenicillin against organisms such as Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Proteus vulgaris, Shigella, Salmonella, Neisseria gonorrhoeae, and Bacteroides fragilis. Most striking are the inhibitory effects of PC-904 against P. aeruginosa and K. pneumoniae. Against these two clinical isolates, PC-904 is, respectively, 35 and 100 times more active than carbenicillin. The minimum inhibitory concentrations of PC-904 against P. aeruginosa are comparable to those of gentamicin. PC-904 acts bactericidally. The effect of inoculum size on the antibacterial activity is often small and generally comparable to carbenicillin. The rate of binding to serum protein is high (88 to 98%), but the effect of the addition of serum on the drug's activity is not marked, because such binding is reversible. It is confirmed that PC-904 has a very potent in vivo antibacterial activity against gram-negative and gram-positive organisms. Against systemic infections with P. aeruginosa, K. pneumoniae, and E. coli in mice, PC-904 is 7 to 10 times, over 8 times, and 2 to 15 times more active than carbenicillin, respectively.

Ampicillin↗
PubMed1998

Bronchoprotective effect of an intrabronchial administration of cilostazol powder and a nebulized PDE1 and PDE4 inhibitor KF19514 in guinea pigs.

BACKGROUND: Both oral and intravenous inhibitors of cyclic nucleotide phosphodiesterase (PDE) 3 and PDE4 have been shown to have bronchodilator and/or pulmonary antiallergic effects but their adverse effects limit the clinical use. The purpose of the present study was to assess the bronchoprotective effect of intrabronchial administration of a selective PDE3 inhibitor, 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quin olinone (cilostazol), in dry power form which is proposed to be desirable rather than propellant-driven metered-dose inhalers. METHODS: Effect of an intrabronchial administration of cilostazol powder on aerosolized histamine- and antigen-induced leukotriene-mediated bronchoconstriction were examined in anesthetized and artificially ventilated guinea pigs, in comparison with the effects of ultrasonically nebulized 5-phenyl-3-(3-pyridyl)methyl-3H-imidazo[4,5-c] [1,8] naphthyridin-4(5H)-one (KF19514), a selective PDE1/4 inhibitor. RESULTS: Cilostazol powder and KF19514 solution inhibited histamine- and antigen-induced bronchoconstriction in a dose-dependent manner. When assessing the resulting ED50 values, the activity of cilostazol powder against antigen-induced broncho-constriction was weaker than its antagonism of histamine-induced bronchoconstriction (60.4 vs. 7.0 microg), while those of KF19514 were the opposite (0.40 vs. 2.81 microg/ml). CONCLUSION: These results suggest that intrabronchially administered cilostazol powder has a bronchodilator effect, and ensure that PDE4 inhibitors have an antiallergic activity in addition to their bronchodilator effect.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1992

Comparative study on the behavioral and EEG changes induced by diazepam, buspirone and a novel anxioselective anxiolytic, DN-2327, in the cat.

Behavioral and EEG effects of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-[(1,4)-dioxa-8-(azas piro-[4.5]dec-8- yl)carbonylmethyl]isoindolin-1-one (DN-2327; 1, 5 and 20 mg/kg p.o.) were compared to those of diazepam (0.2 and 1 mg/kg p.o.) and buspirone (1 and 5 mg/kg p.o.) in freely moving cats. DN-2327 did not affect motor coordination or the relative percentages of the three sleep-wakefulness stages. Diazepam (1 mg/kg) increased wakefulness and non-REM sleep, and buspirone (5 mg/kg) also increased wakefulness and decreased REM sleep. In addition, diazepam (1 mg/kg) caused severe motor disturbance, but buspirone did not. The cortical EEG power density spectra during wakefulness were changed almost dose-dependently by DN-2327 (decreased: 2-7.75 Hz; increased: 20-49.75 Hz), and dose-dependently by diazepam (decreased: 2-7.75 Hz; increased 13-49.75 Hz) and buspirone (decreased: 4-9.75 and 13-19.75 Hz). The effect of DN-2327 on the cortical EEG varied with the sleep-wakefulness stage. The power of the 4- to 7.75-Hz frequency (theta) band of the hippocampal EEG during wakefulness was decreased by diazepam and buspirone but not by DN-2327, while the peak frequency of its spectra was decreased only by diazepam. On the other hand, during non-REM sleep, DN-2327 decreased the power of the theta band as did diazepam. These results indicate that the behavioral and EEG effects of DN-2327 differ completely from those of buspirone and considerably from those of diazepam and that the EEG effect of DN-2327 varies with the sleep-wakefulness stage.

Animals↗
PubMed1997

KF19514, a phosphodieterase 4 and 1 inhibitor, inhibits PAF-induced lung inflammatory responses by inhaled administration in guinea pigs.

Phosphodiesterase (PDE) 4 inhibitors are well known for their inhibitory effect on bronchoconstriction and inflammation and may be promising anti-asthma drugs. Platelet-activating factor (PAF) has been proposed as an inflammatory mediator to be relevant to asthma. It causes bronchoconstriction, airway microvascular leakage, inflammatory cell accumulation in the lung and hyperresponsiveness. In this study, we therefore have investigated the anti-asthmatic effects of the inhaled KF19514 [5-phenyl-3'-(3-pyridyl)methyl-3H-imidazo(4,5-c)(1,8) naphthyridin-4(5H)-one], a PDE 4 and 1 inhibitor, on PAF-induced lung inflammatory responses in guinea pigs. The inhaled KF19514 (0.0001-0.01%) significantly inhibited PAF-induced eosinophil and neutrophil accumulation into the airway and hyperresponsiveness in guinea pigs. The IC50 value of KF19514 against eosinophil accumulation was 14.8 microM (0.00063%). Moreover, the effect of KF19514 on the electrical field stimulation-induced bronchial contraction was examined using the main bronchi of guinea pigs in vitro. KF19514 inhibited both cholinergic and tachykininergic contraction and, in particular, produced a potent inhibitory effect on tachykininergic contraction (IC50 = 0.49 microM). The mechanism by which KF19514 inhibited the PAF-induced hyperresponsiveness may in part be the suppression of the tachykinin release. Based on these results, it was demonstrated that the inhaled KF19514 might have a significant potential effect on the inflammatory cell accumulation and hyperresponsiveness induced by PAF.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2003

[Structure activity relation study of matrine-type alkaloids. Part III].

6-Acyldecahydro [1,6]naphthyridines were synthesized as derivatives of matrine-type and allomatrine-type alkaloids, and the structure-activity relations were examined by the acetic acid-induced abdominal contraction test. All synthesized derivatives produced the antinociception in mice. The antinociceptive potencies of 15a-c and 16a-c were lower than those of 17a-c, 18a-c, 19a-c and 20a-c. Furthermore, those of the matrine-type derivatives 17b and 17c are greater than other derivatives. These findings suggest that less hindered tertiary amine and highly lipophilic acyl group are better functional groups for the greater antinociceptive potencies. Furthermore, these findings suggest that A or B ring of 1 and 2 are not essential for the antinociceptive effect.

Analgesics↗
PubMed1989

[Adverse drug interactions between pyridonecarboxylic acids and nonsteroidal antiinflammatory drugs: convulsion after oral or intracerebral administration in mice].

Comparing with other pyridonecarboxylic acids (PCAs), the neurotoxicity of (+/-)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4- dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid p-toluenesulfonate hydrate (T-3262), which is a new PCA, was investigated in mice in a combination with fenbufen (FBF). T-3262, ofloxacin (OFLX) and nalidixic acid (NA) did not produce convulsion, but enoxacin (ENX) and norfloxacin (NFLX) produced it after an oral administration with FBF. The intracerebral injection of drugs alone to mice revealed that both FBF and 4-biphenylacetic acid (BPAA), which is principally responsible for FBF's antiinflammatory action, scarcely had convulsant activity. While all the PCAs had convulsant activity and the order of potency was as follows; NFLX greater than ENX greater than OFLX greater than penicillin G potassium greater than the free base of T-3262 (T-3262 base) greater than or equal to NA. When orally pretreated with BPAA, the convulsive threshold was scarcely lowered for T-3262 base and OFLX, but for ENX and NFLX it was lowered to about 1/300 and 1/100 of the respective activity. As the result, convulsant activities of ENX and NFLX were greatly potentiated, and their potencies became almost equal. The adverse drug interactions between T-3262 and FBF were scarcely observed in mice.

4-Quinolones↗
PubMed1989

Pharmacologic characterization of a novel non-benzodiazepine selective anxiolytic, DN-2327.

DN-2327, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-[(1,4-dioxa-8- azaspiro[4.5]dec-8-yl)carbonylmethyl]isoindolin-1-one, produced anxiolytic, taming and anti-convulsive effects when administered orally to several species of animals. DN-2327 produced few of the sedative-hypnotic and muscle-relaxant effects observed with diazepam. The durations of the anxiolytic and anti-convulsive activities of DN-2327 were much longer than those of diazepam. Tolerance to DN-2327 did not develop when it was administered daily for 14 days in an anti-conflict test (Vogel conflict test). DN-2327 showed potent displacement activity against [3H]diazepam binding. The binding affinity of DN-2327 for benzodiazepine receptors was about twenty times that of diazepam. Furthermore, the affinity of DN-2327 for benzodiazepine receptors was not enhanced by the presence of GABA. There is a wide margin between the doses of DN-2327 that cause the anxiolytic effects and its sedative-hypnotic/muscle-relaxant effects. These results suggest that DN-2327 has more marked anxioselective properties compared with the benzodiazepines.

Aggression↗