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A 1,6-naphthyridine inhibitor of HIV-1 integrase has been discovered with excellent inhibitory activity in cells, good pharmacokinetics, and an excellent ability to inhibit virus with mutant enzyme.
T-0156 (2-(2-methylpyridin-4-yl)methyl-4-(3,4,5-trimethoxyphenyl)-8-(pyrimidin-2-yl)methoxy-1,2-dihydro-1-oxo-2,7-naphthyridine-3-carboxylic acid methyl ester hydrochloride) is a newly synthesized phosphodiesterase type 5 inhibitor, and its potency and selectivity are higher than those of sildenafil in an enzyme assay. In the present study with anesthetized dogs, we examined the effects of intravenous T-0156 or sildenafil on the pelvic nerve stimulation-induced penile tumescence and light-adapted flicker stimulation-induced electroretinogram, parameters of which are reported to be indicators for inhibition of phosphodiesterase type 5 and type 6, respectively. Both compounds potentiated the penile tumescence in a dose-dependent manner. T-0156 at 10 microg/kg and sildenafil at 100 microg/kg showed almost the same potentiating percentage (181.5+/-31.1% and 190.0+/-37.9%) in spite of the plasma concentration of T-0156 being about five times lower than that of sildenafil (16.7+/-1.6 and 78.8+/-5.3 ng/ml), indicating that the effect of T-0156 on tumescence is more potent than that of sildenafil. While the high dose of T-0156 (1000 microg/kg) reduced the amplitude and increased the latency of the electroretinogram positive wave, the effects of T-0156 were conversely weaker than those of sildenafil (reduction of amplitude; T-0156: 41.1+/-8.0%, sildenafil: 71.7+/-3.9%, increase of latency; T-0156: 3.9+/-0.6%, sildenafil: 14.5+/-1.4%, at 1000 microg/kg). These results clearly showed the difference in the properties of T-0156 and sildenafil in pharmacological studies with anesthetized dogs, and the difference appeared to correspond with their inhibitory potencies for phosphodiesterase type 5 and type 6. It was concluded that T-0156 would be a useful pharmacological tool as a potent and highly selective phosphodiesterase type 5 inhibitor.
Serotonin (5-HT)(1A) receptor agonists have been reported to produce mydriasis in mice, and miosis in rabbits and humans. However, the underlying mechanisms for this action are unclear. This study was undertaken in an attempt to explore the mechanism by which 5-HT(1A) receptors are involved in the modulation of pupillary size in pentobarbital-anesthetized rats. Intravenous administration of the 5-HT(1A) receptor agonist, (2R)-(+)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT; 0.003-3 mg/kg), elicited dose-dependent pupillary dilation, which was not affected by section of the preganglionic cervical sympathetic nerve. 8-OH-DPAT-elicited mydriatic responses were attenuated by the selective 5-HT(1A) receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate (WAY 100635; 0.3-1 mg/kg, i.v.), as well as by the selective alpha(2)-adrenoceptor antagonist, (8aR,12aS,13aS)-5,8,8a,9,10,11,12,12a,13,13a-dechydro-3-methoxy-12-(ethylsulfonyl)-6H-isoquino[2,1-g][1,6]naphthyridine hydrochloride (RS 79948; 0.3 mg/kg, i.v.), but not by the selective alpha(1)-adrenoceptor antagonist, prazosin (0.3 mg/kg, i.v.). Mydriatic responses elicited by the alpha(2)-adrenoceptor agonist, guanabenz (0.003-0.3 mg/kg, i.v.), were not antagonized by WAY 100635 (0.3-1 mg/kg, i.v.). To determine whether central nervous system (CNS) 5-HT(1A) receptors, like alpha(2)-adrenoceptors, are involved in reflex mydriasis, voltage response curves of pupillary dilation were constructed by stimulation of the sciatic nerve in anesthetized rats. WAY 100635 (1 mg/kg, i.v.) did not antagonize the evoked reflex mydriasis, which, however, was blocked by RS 79948 (0.3 mg/kg, i.v.). Taken together, these results suggest that 8-OH-DPAT produces pupillary dilation in anesthetized rats by stimulating CNS 5-HT(1A) receptors, which in turn trigger the release of norepinephrine, presumably from the locus coeruleus. The latter reduces parasympathetic neuronal tone to the iris sphincter muscle by stimulation of postsynaptic alpha(2)-adrenoceptors within the Edinger-Westphal nucleus. Unlike alpha(2)-adrenoceptors, 5-HT(1A) receptors in the CNS do not mediate reflex mydriasis evoked by sciatic nerve stimulation.
[Ethyl-(3)H][8aR,12aS,13aS]-5,8,8a,9,10,11,12,12a,13,13a-decahydro-3-methoxy-12-(ethylsulfonyl)-6H-isoquino[2,1-g][1,6]naphthyridine ([ethyl-(3)H]RS-79948-197) was evaluated for alpha(2)-adrenoceptor autoradiography in brain sections from wild-type mice and alpha(2A)- and alpha(2ABC)-adrenoceptor knockout mice. Receptor numbers were 83% lower in cortex and 28% lower in caudate putamen of alpha(2A)-knockout mice than in wild-type mice. No specific binding was seen in alpha(2ABC)-knockout mice. [Ethyl-(3)H]RS-79948-197 saturation binding parameters were compared to those of [(3)H]2-(2,3-dihydro-2-methoxy-1,4-benzodioxan-2-yl)-4,5-dihydro-1H-imidazoline ([(3)H]RX821002) and [methyl-(3)H]17alpha-hydroxy-20alpha-yohimban-16beta-carboxylic acid methyl ester ([methyl-(3)H]rauwolscine). [Ethyl-(3)H-]RS-79948-197 detected a larger number of both alpha(2A)- and alpha(2B/C)-adrenoceptors than [(3)H]RX821002, while [methyl-(3)H]rauwolscine only underestimated the number of alpha(2A)-adrenoceptors. Oxymetazoline and prazosin competed for [ethyl-(3)H]RS-79948-197 binding with the expected rank order of affinities. Higher than necessary [ethyl-(3)H]RS-79948-197 concentrations resulted in a rapid increase in non-specific binding. Slow dissociation kinetics, high specific radioactivity and high alpha(2)-adrenoceptor affinity (slightly lower for the alpha(2A)-adrenoceptor than for the other subtypes) confer [ethyl-(3)H]RS-79948-197 distinct advantages compared to [(3)H]RX821002 for detection of alpha(2)-adrenoceptor subtypes in a mixed alpha(2)-adrenoceptor population.
The pharmacological mechanism of bupropion's thermogenic effect has been investigated in female Wistar rats by measuring oxygen consumption at thermoneutrality (29 degrees C). Bupropion (30 mg/kg) rapidly increased oxygen consumption (VO2) with a maximum effect at 30 min, and VO2 remained elevated throughout the 4-h experimental period. The nonselective 5-hydroxytryptamine (5-HT or serotonin) receptor antagonist, metergoline (1 mg/kg), and the alpha1-adrenoceptor antagonist, prazosin (1 mg/kg), had no effect on the VO2 response to bupropion, whereas the alpha2-adrenoceptor antagonist, RS79948 [(8aR, 12aS, 13aS)-5,8,8a,9,10,11,12,12a,13,13a-decahydro-3-methoxy-12-(ethylsulphonyl)-6H-isoquino[2,1-g][1,6]-naphthyridine hydrochloride] (1 mg/kg), potentiated the response. The VO2 response to bupropion during the first 60 min was significantly inhibited by a high dose of the nonselective beta-adrenoceptor antagonist, propranolol (20 mg/kg), but it had no effect at a low dose (1 mg/kg). Pretreatment with the dopamine D2/D1 receptor antagonist, (+)butaclamol (200 microg/kg), caused a partial, but significant, inhibition (P<0.01) of the VO2 response to bupropion during the first 60 min, and this antagonist abolished the effect of bupropion between 90 and 240 min. Pretreatment with a combination of a high dose of propranolol (20 mg/kg) and (+)butaclamol (200 microg/kg) prevented any increase in VO2 induced by bupropion. It is concluded that the beta3-adrenoceptor subtype, as well as dopamine D2/D1 receptors, is responsible for the increase in oxygen consumption induced by bupropion. We have previously demonstrated that bupropion did not significantly reduce food intake in rats. Hence, in this species, its weight-reducing action predominantly results from thermogenesis mediated via activation of beta3-adrenergic and dopamine D2/D1 receptors. Because bupropion has also been reported not to alter food intake in the clinic, thermogenesis may also contribute to its antiobesity effect in man.
Poly (ADP-ribose) polymerase-1 (PARP-1), a nuclear enzyme activated by DNA strand breaks, plays a detrimental role during inflammation. As inflammation is important in the development of colitis and ischemia/reperfusion (I/R) injury of the intestine, we investigated the effects of 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de]anthracen-3-one (GPI 15427) and 2-(4-methyl-piperazin-1-yl)-5H-benzo[c][1,5]naphthyridin-6-one (GPI 16539), two novel and potent inhibitors of PARP-1, in a rat model of gut injury and inflammation, splanchnic artery occlusion (SAO)shock and dinitrobenzene sulfonic acid (DNBS)-induced colitis. We report here for the first time that post-injury administration of GPI 15427 and GPI 16539 exerts potent anti-inflammatory effects by reducing inflammatory cell infiltration and histological injury, and delaying the development of clinical signs in both in vivo models. Furthermore, GPI 15427 and GPI 16539 treatment diminished the accumulation of poly(ADP-ribose) in the ileum of splanchnic artery occlusion-shocked rats and in the colons of dinitrobenzene sulfonic acid-treated rats. Thus, GPI 15427 and GPI 16539 exhibited anti-inflammation activity against damage caused by intestinal ischemia/reperfusion and colitis. GPI 15427 and GPI 16539 may be useful for treating gut ischemia and inflammation.
An HPLC-MS/MS assay for the determination of an HIV integrase inhibitor, 5-(1,1-dioxido-1,2-thiazinan-2-yl)-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide (I) in human plasma has been developed and validated. Compound I and a stable isotope labeled internal standard (II) were isolated from 0.5 mL plasma samples by solid phase extraction using an Ansys SPEC C-8 96-well plate. Extracts were separated on a Hypersil BDS C-18 HPLC column (3.0 mmx50 mm, 3 microm) with a mobile phase consisting of 25 mM ammonium formate pH 3.0:acetonitrile (60:40) vol%/vol% pumped at 0.5 mL/min. A Sciex API 365 mass spectrometer equipped with an atmospheric pressure chemical ionization source was operated in selected reaction monitoring (SRM) mode with the precursor-to-product ion transitions m/z 431-->109 (I) and m/z 437-->115 (II) used for quantitation. The assay was validated over the concentration range of 10-5000 ng/mL and was found to have acceptable accuracy, precision, linearity, and selectivity. The mean extraction recovery from spiked plasma samples was 69%. The intra-day accuracy of the assay was within 4% of nominal and intra-day precision was better than 4% C.V. Following a 200 mg dose of the compound administered to human subjects, concentrations of I ranged from 21.1 to 1500 ng/mL in plasma samples collected up to 12 h after dosing. Inter-day accuracy and precision results for quality control samples run over a 3-month period alongside clinical samples showed mean accuracies of within 6% of nominal and precision better than 3.5% C.V.
The effects of a new tachykinin NK(1) receptor antagonist, (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 (TAK-637), on the micturition reflex were compared with those of drugs used for abnormally frequent micturition or incontinence. TAK-637 showed a characteristic effect on the distension-induced rhythmic bladder contractions in guinea pigs. The systemic administration of TAK-637 decreased the number but not the amplitude of the distension-induced rhythmic bladder contractions. A similar effect was observed in animals in which the spinal cord had been severed. TAK-637 also inhibited the micturition reflex induced by topical application of capsaicin onto the surface of bladder dome. From these results, it is concluded that TAK-637 inhibits sensory transmissions from the bladder evoked by both physiological and nociceptive stimuli by blocking tachykinin NK(1) receptors, possibly at the level of the spinal cord. On the other hand, the other drugs such as oxybutynin, tolterodine, propiverine, and inaperisone showed no effects on the frequency of the distension-induced rhythmic bladder contractions but decreased the contraction amplitude. Therefore, TAK-637 may represent a new class of drugs, which would be effective for abnormally frequent micturition without causing voiding difficulties due to decreased voiding pressure.
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) is a novel tachykinin NK(1) receptor antagonist that has been shown to inhibit the micturition reflex in guinea pigs. The aim of this study was to clarify its mechanism of action in guinea pigs. TAK-637 inhibited the spinal vesico-vesical reflex induced by electrical stimulation of the proximal cut end of the pelvic nerve in spinal animals, but not bladder contractions induced by electrical stimulation of the distal cut end of the nerve. Furthermore, TAK-637 had no effect on carbachol- or electrical field stimulation-induced contractions of isolated bladder muscle strips in an organ bath, whereas drugs used for abnormally frequent micturition inhibited both contractions. These results suggest that TAK-637 inhibits the micturition reflex by acting, at least in part, on the spinal cord, and its mechanism of action clearly differs from those of antimuscarinics or spasmolytics.
Tryptase, a serine protease synthesized by and stored in mast cells, is implicated as an important mediator in the pathogenesis of airway inflammation. In this study, tryptase was evaluated for its ability to induce microvascular leakage into the airways of guinea pigs. Dose- and time-dependent increases in airway microvascular leakage were produced by intratracheal tryptase (0.3-3 microg). Intratracheal tryptase (3-30 microg) had no effect on airway tone as measured by pulmonary insufflation pressure. Tryptase-induced airway microvascular leakage was partially blocked by the tachykinin NK1 receptor antagonist CP 99994 [(+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine] and an inhibitor of leukotriene formation SCH 37224 (1-(1,2-dihydro-4-hydroxy-2-oxo-1-phenyl-1,8-naphthyridin-2-yl)pyrrolidinium, hydroxide inner salt). Neither CP 99994 nor SCH 37224 inhibited tryptase proteolytic activity in-vitro. Pretreatment of guinea pigs with histamine H1 receptor antagonists or a tachykinin NK2 receptor antagonist had no affect on the airway microvascular leakage induced by tryptase. It is speculated that tryptase may be important in the pathogenesis of airway inflammation, particularly in disorders that involve increased airway microvascular leakage such as asthma.
In this study, alpha(1)-adrenoceptor subtypes were characterised in rat femoral resistance arteries mounted on a small vessel myograph. A-61603 was found to be more potent than noradrenaline and phenylephrine in these arteries. Brimonidine (UK 14304) could not evoke any contractile responses and the sensitivity to noradrenaline and phenylephrine was not affected by (8aR,12aS,13aS)-5,8,8a,9,10,11,12,12a,13a-decahydro-3-methoxy-12-(ethylsulphonyl)-6H-isoquino[2,1-g][1,6]-naphthyridine (RS 79948), ruling out the presence of alpha(2)-adrenoceptors. Prazosin, 5-methyl-urapidil and 2-([2,6-dimethoxyphenoxyethyl]aminomethyl)-1,4-benzodioxane (WB 4101) produced rightward shifts in the sensitivity to noradrenaline, giving pA(2) values of 9.6, 9.4 and 10.4, respectively, in agreement with the presence of alpha(1A)-adrenoceptors. (8-[2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione (BMY 7378; 1 microM) produced a small shift in the sensitivity of noradrenaline giving a pK(B) of 7.2. In the presence of 300 nM 5-methyl-urapidil, sensitivity to noradrenaline was not further shifted by 1 microM BMY 7378. Responses to noradrenaline were unaffected by the alpha(1B)-adrenoceptor alkylating agent chloroethylclonidine (1 microM). These results suggest alpha(1A)-adrenoceptors mediate contractile responses to noradrenaline in rat femoral resistance arteries.
The regulation of noradrenaline release in the rat cingulate cortex by somatodendritic alpha(2)-adrenoceptors placed in the locus coeruleus was evaluated by dual-probe microdialysis. The alpha(2)-adrenoceptor antagonists BRL44408 (2-[2H-(1-methyl-1,3-dihydroisoindole)methyl]-4,5-dihydroimidazole), RS79948 ((8,12,13)-decahydro-3methoxy-12-(ethylsulphonyl)-6H-isoquino[2,1-g][1,6]-naphthyridine) and RX821002 (2-methoxyidazoxan) administered by reverse dialysis into the locus coeruleus increased concentration-dependently (0.01-100 microM) noradrenaline release in the cortex (maximal effects 170+/-30%, 543+/-17%, 195+/-26%, respectively). Administration of the alpha(2)-adrenoceptor antagonist idazoxan increased at lower (0.1-10 microM) but decreased at the highest dose (100 microM) noradrenaline in the cortex. These data demonstrate that somatodendritic alpha(2)-adrenoceptors in the locus coeruleus exert an inhibitory tonic modulation on noradrenaline release in noradrenergic terminal areas.
The enzymological and pharmacological properties of 2-(2-Methylpyridin-4-yl)methyl-4-(3,4,5-trimethoxyphenyl)-8-(pyrimidin-2-yl)methoxy-1,2-dihydro-1-oxo-2,7-naphthyridine-3-carboxylic acid methyl ester hydrochloride (T-0156), a new phosphodiesterase type 5 inhibitor, were studied in vitro and in vivo. The inhibitory effects of T-0156 on six phosphodiesterase isozymes isolated from canine tissues were investigated. T-0156 specifically inhibited the hydrolysis of cyclic guanosine monophosphate (cGMP) by phosphodiesterase type 5, at low concentration (IC(50)=0.23 nM), in a competitive manner. T-0156 also inhibited phosphodiesterase type 6 with IC(50) value of 56 nM, which was 240-fold higher than that for inhibition of phosphodiesterase type 5. T-0156 had low potencies against phosphodiesterase types 1, 2, 3, and 4 (IC(50)>10 microM). In the isolated rabbit corpus cavernosum, T-0156 at 10 and 100 nM increased cGMP levels (100 nM T-0156-treated: 6.0+/-1.5 pmol/mg protein, vehicle-treated: 1.1+/-0.4 pmol/mg protein, P<0.05), causing relaxation of the tissue. T-0156 at 1 to 100 nM potentiated the electrical field stimulation-induced relaxation in the isolated rabbit corpus cavernosum in a concentration-dependent manner (100 nM T-0156-treated: 76.9+/-19.8%, vehicle-treated: 12.3+/-10.1%, P<0.05). Intraduodenal administration of T-0156 at 100 to 1000 microg/kg potentiated the pelvic nerve stimulation-induced tumescence in anesthetized dogs (1000 microg/kg T-0156-treated: 279.0+/-38.4%, vehicle-treated: 9.8+/-4.5%, P<0.05). These results suggested that T-0156 enhanced the nitric oxide (NO)/cGMP pathway, probably through blockade of phosphodiesterase type 5 in vitro and in vivo experimental conditions. The present study clearly showed that T-0156 is a potent and highly selective phosphodiesterase type 5 inhibitor, which is a useful tool for pharmacological studies in vitro and in vivo.
Tritium-labelled RS-79948-197 {(8aR,12aS,13aS)-5, 8,8a,9,10,11,12,12a,13,13a-decahydro-3-methoxy-12-(ethylsulphon yl)-6H-iso- quino[2,1-g][1,6]naphthyridine} was evaluated in rat brain as an in vivo ligand for central alpha 2-adrenoceptors, as a preliminary step in the development of a radioligand for positron-emission tomography (PET) studies. The maximal receptor-specific signal was achieved within 90-120 min after i.v. injection of [ethyl-3H]RS-79948-197 and was selective for the alpha 2- compared with the alpha 1-adrenoceptor, with no detectable binding to the imidazoline-I2 site. Estimates for binding potential (approximating to Bmax/Kd) ranged between 3.4 in entorhinal cortex and 0.5 in medulla oblongata. The results, which indicate a similarly localised but 2-fold increase in specific binding compared with that previously demonstrated using [3H]RX 821002 (2-methoxy-idazoxan), are sufficiently encouraging as to support further investment in the development of 11C-labelled RS-79948-197, or a close structural analogue, as a ligand for clinical PET.
We investigated the effects of KF19514 (5-phenyl-3-(3-pyridyl)methyl-3H-imidazo[4,5-c][1,8]naphthyridin-4 (5H)-one) on bronchoconstriction and allergic inflammation in guinea pigs and on tumor necrosis factor-alpha production in mice. KF19514 inhibited phosphodiesterase 4 (IC50 = 0.40 microM) and phosphodiesterase 1 (IC50 = 0.27 microM) derived from canine tracheal smooth muscles. KF19514 relaxed contracted tracheal smooth muscle and had a potent inhibitory effect on antigen-induced bronchoconstriction (EC50 = 0.058 microM) in vitro. Intravenous administration of KF19514 inhibited histamine-induced bronchoconstriction (ID50 = 2.8 microg/kg i.v.). Moreover, oral administration of KF19514 inhibited anaphylactic bronchoconstriction (ID50 = 0.2 mg/kg p.o.), and eosinophil infiltration in airway stimulated with platelet-activating factor (PAF) or antigen. KF19514 also produced a significant inhibition of tumor necrosis factor-alpha production in mice (ID50 = 0.023 mg/kg p.o.). Finally, KF19514 completely inhibited antigen-induced hyperreactivity at 0.1 mg/kg p.o. These results demonstrate that KF19514 may have efficacy in the treatment of asthma.
The Kd values of the recently introduced radioligand [3H]RS79948-197 ((8a R,12aS,13a-S)-5,8,8a,9,10,11,12,12a,13,13a-decahydro-3-metho xy-12-(ethylsulphonyl)-6H-isoquino[2,1-g][1,6]naphthyridine) were determined for the recombinant human and rat alpha2A-, alpha2B- and alpha2C- as well as guinea pig alpha2B- and alpha2c-adrenoceptors expressed in COS (CV-1 Origin, SV40) cells. In addition, the Kd values were also determined for [3H]RS79948-197 for the guinea pig spleen alpha2A-adrenoceptor and for pig alpha2A-, alpha2B- and alpha2C-adrenoceptors in membranes obtained from kidney and striatum. Available radioligands for alpha2-adrenoceptors, besides [3H]RS79948-197 are the tritiated forms of MK912 ((2S,12bS)1',3'-dimethylspiro(1,3,4,5',6,6',7,12b-octa hydro-2H-benzo[b]furo[2,3-a]quinazoline)-2,4'-pyrimidin-2'-one), RX821002 (2-methoxy-idazoxan), rauwolscine and yohimbine. In the present article the binding constants of all these substances for the alpha2A-, alpha2B- and alpha2C-adrenoceptor subtypes in human, pig, rat and guinea pig are reviewed. In all species tested MK912 was alpha2C-selective, RX821002 showed a minor alpha2A-selectivity, whereas [3H]RS79948-197 was non-selective among the alpha2-adrenoceptor subtypes, showing high affinity for all three subtypes. Rauwolscine and yohimbine showed relatively low affinities for nmost of the alpha2-adrenoceptor subtypes investigated, the exception being rauwolscine having high affinity for the human and porcine alpha2C-adrenoceptors.
It has been shown that inhibitors of cyclic nucleotide phosphodiesterase III and IV have a bronchodilator effect. We compared the effects of a selective phosphodiesterase III inhibitor, 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quin olinone (cilostazol) and a phosphodiesterase I/IV inhibitor, 5-phenyl-3-(3-pyridil) methyl-3H-imidazo[4,5-c][1,8]naphthyridin-4(5H)-one (KF-19514) on antigen- and histamine-induced bronchoconstriction in guinea pigs in vivo. Intravenous administration of cilostazol and KF-19514 inhibited histamine- and antigen-induced bronchoconstriction in a dose-dependent manner. When assessing the resulting ED50 values, the activity of KF-19514 against antigen-induced bronchoconstriction was stronger than its antagonism of histamine-induced bronchoconstriction (0.004 vs. 0.056 mg/kg). while those of cilostazol were contrary (0.835 vs. 0.031 mg/kg). These results suggest that although both inhibitors of phosphodiesterase III and phosphodiesterase IV have a bronchodilator or bronchoprotective effect, phosphodiesterase IV inhibitors such as KF-19514 may be more useful for asthma treatment because KF-19514 had an anti-allergic effect in addition to the functional bronchodilator activity.
The effects of 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), a novel tachykinin NK(1) receptor antagonist, on the micturition reflex in guinea pigs were studied in comparison with those of anti-pollakiuria agents. Cystometry was performed under urethane anesthesia. TAK-637 increased the volume threshold with a minimum effective dose of 0.03 mg/kg, i.v. without affecting voiding pressure. Oxybutynin, tolterodine, propiverine and inaperisone also increased the volume threshold in urethane-anesthetized guinea pigs, but they decreased voiding pressure, although the effect of propiverine was not statistically significant. A structurally unique tachykinin NK(1) receptor antagonist, (+/-)-CP-99,994 ((+/-)-(2S, 3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine), increased the volume threshold with a minimum effective dose of 0.3 mg/kg, i.v. TAK-637 increased the volume threshold with a minimum effective dose of 0.01 mg/kg, p.o. in unanesthetized guinea pigs. These results indicate that TAK-637 may be useful as pharmacotherapy for detrusor overactivity without decreasing voiding pressure or causing voiding difficulties.