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T Abiru

Publications and source records attributed to T Abiru.

16 recordsLinked to original sources
PubMed1992

Nucleosides and nucleotides. 112. 2-(1-Hexyn-1-yl)adenosine-5'-uronamides: a new entry of selective A2 adenosine receptor agonists with potent antihypertensive activity.

Chemical modifications of the potent A2 adenosine receptor agonist 2-(1-hexyn-1-yl)adenosine (7, 2-HA) at the 5'-position have been carried out to find more potent and selective A2 agonists. These analogues were evaluated for adenosine A1 and A2 receptor binding affinity in rat brain tissues and antihypertensive effects in spontaneously hypertensive rats (SHR). Among the series of compounds, 2-(1-hexyn-1-yl)adenosine-5'-N-cyclopropyluronamide (16d) had the most potent affinity to the A2 receptor with a Ki of 2.6 nM, which is essentially the same as that of the parent agonist, 2-HA. However, the most selective agonist for the A2 receptor was 2-(1-hexyn-1-yl)adenosine-5'-N-methyluronamide (16b) with a Ki of 11 nM and a 162-fold selectivity. The N-alkyl substituents of 5'-uronamide derivatives did not seem to potentiate the A2 binding affinity but drastically reduced the A1 affinity compared with the parent 2-HA. Therefore, the A1/A2 selectivity was consequently increased. Other 5'-deoxy-5'-substituted derivatives of 2-HA such as the chloro (20), carboxamide (27, 28), sulfonamide (29), urea (30), and thiourea (22) analogues were also prepared. Among these nucleosides, no active compounds with potent or selective affinities to both receptors were found except 20. Although glycosyl conformations and sugar-puckering of these nucleosides were studied by 1H NMR spectroscopy, there were no positive correlations between active and inactive agonists. 2-(1-Hexyn-1-yl)adenosine-5'-uronamide (16a) and 16d had a potent hypotensive effect at ED30 values of 0.18 and 0.17 micrograms/kg, respectively, upon iv administration to anesthetized SHR.

Adenosine↗
PubMed1992

Nucleosides and nucleotides. 107. 2-(cycloalkylalkynyl)adenosines: adenosine A2 receptor agonists with potent antihypertensive effects.

Adenosine receptor-binding profiles in rat brain tissues and antihypertensive effects in spontaneously hypertensive rats (SHR) of a series of 2-(cycloalkylalkynyl)adenosines (2-CAAs) and their congeners are described. The structure-activity relationship of this series of compounds is discussed, focusing on the length of the alkynyl side chain and bulkiness of the terminal cycloalkyl substituents in terms of binding activity and cardiovascular effects. All the 2-CAAs had a preferential affinity for A2 receptors. Of these derivatives, 2-(3-cyclopentyl-1-propyn-1-yl)adenosine (10b) exhibited the most selective affinity for A2 receptors (Ki ratio: A1/A2 = 70) on the basis of receptor binding. In the C-2 binding region of adenosine, compounds often have potent and/or selective A2 activity from introduction of an acetylenic group at the C-2 position followed by one methylene residue further followed by a hydrophobic substituent such as a cycloalkyl ring at the terminal position of the alkynyl side chain. Intravenous injection of 10b up to 100 micrograms/kg had a potent hypotensive effect without a marked decrease in heart rate in anesthetized SHR. Compounds 10j-s, with a hydroxyl group in the C-3" position of the alkynyl side chain, had a potent affinity for both A1 and A2 receptors, but they were not highly selective for A2 receptors. These compounds caused a marked bradycardia upon intravenous administration in anesthetized SHR. Oral administration of 10b (0.1-1 mg/kg) had a potent and long-lasting antihypertensive effect in conscious SHR.

Adenosine↗
PubMed1992

Nucleosides and nucleotides. 103. 2-Alkynyladenosines: a novel class of selective adenosine A2 receptor agonists with potent antihypertensive effects.

The synthesis and receptor-binding activities at A1 and A2 adenosine receptors for a series of 2-alkynyladenosines are described. The palladium-catalyzed cross-coupling reaction of 2-iodoadenosine (4a) with various terminal alkynes in the presence of bis(triphenylphosphine)palladium dichloride and cuprous iodide in N,N-dimethylformamide containing triethylamine gives 2-alkynyladenosines (5a-r). An economical synthetic method for the preparation of 9-(2,3,5-tri-O-acetyl-1-beta-D-ribofuranosyl)-6-chloro-2-iodopurine++ + (2), which is a precursor of 4a, is also included. Several transformation reactions of 2-(1-octyn-1-yl)adenosine (5e) and 2-(1-ethyn-1-yl)adenosine (9) and a similar cross-coupling reaction of 6-chloropurine derivative 11 and 8-bromoadenosine (13) with 1-octyne are also reported. Many of these 2-alkynyladenosines tested for A1 and A2 adenosine receptor binding activities in rat brain are selective for the A2 adenosine receptor. Among them, 2-(1-hexyn-1-yl)adenosine (5c) has the highest affinity for both A1 and A2 receptors with Ki values of 126.5 and 2.8 nM, respectively. The structure-activity relationship of this series of compounds including 6- or 8-alkynylpurine nucleosides and 2-alkyl- and 2-alkenyladenosines is discussed in terms of potency at both receptor subtypes. Additionally, we describe how hypotensive activity and heart rate decrease brought on by 5 and some other compounds with spontaneously hypertensive rats are proportional to the order of the potency to both A1 and A2 binding affinities. Thus, 2-alkynyladenosines are interesting and promising as antihypertensive agents that should be considered for further detailed preclinical evaluation.

Adenosine↗
PubMed1992

Functional changes in vascular smooth muscle and endothelium of arteries during diabetes mellitus.

To investigate the influence of diabetes mellitus on the responsiveness of the vascular smooth muscle, the effects of various vasoactive agents on the reactivity of the vascular smooth muscle from diabetic animals have been undertaken, focusing on the functional changes in the endothelium, alpha-adrenoceptors, beta-adrenoceptors, voltage-dependent Ca(2+)-channels, receptor-operated Ca(2+)-channels, phosphatidylinositol turnover and potassium channels. Among the functional changes, it is a common phenomenon that decreases in acetylcholine-induced production of cyclic GMP are due to the attenuation of release of endothelium-derived relaxing factor through an impairment of endothelium; this observation was found in both rats and rabbits with diabetes mellitus. These functional changes in diabetes may be responsible for the vascular complications such as coronary heart disease, cerebrovascular disease, and an acceleration in atherosclerosis.

Animals↗
PubMed1992

Influences of cyclooxygenase inhibitors on the cataleptic behavior induced by haloperidol in mice.

Haloperidol administered intraperitoneally, and prostaglandin F2 alpha (PGF2 alpha) and PGE2 intraventricularly induced dose-dependent cataleptic behavior in mice. The cataleptic behavior induced by haloperidol was inhibited dose-dependently by oral pretreatment with aspirin and indomethacin, inhibitors of PGs synthetase. Striatal 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindole 3 acetic acid (5-HIAA) were elevated by haloperidol, although dopamine (DA) and 5-hydroxytryptamine (5-HT) levels did not change. The increase of DOPAC level in striatum induced by haloperidol was significantly suppressed by aspirin, but not in brain stem. The alteration of DOPAC level by aspirin correlated with the behavioral response. These results suggest that central prostaglandin synthesis may participate in the development of cataleptic behavior, which might also involve alteration of brain catecholaminergic activity.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

The antihypertensive effect of 2-alkynyladenosines and their selective affinity for adenosine A2 receptors.

We examined the affinity for adenosine receptors and the antihypertensive effects of 2-alkynyladenosines, especially 2-hexynyladenosine (2-H-Ado) and 2-octynyladenosine (2-O-Ado). The order of decreasing affinity of 2-H-Ado, 2-O-Ado, and other agonists tested for A1 receptors was N6-cyclopentyladenosine (CPA) greater than N6-cyclohexyladenosine (CHA) greater than N6-R-phenylisopropyladenosine (R-PIA) greater than 2-chloroadenosine (CADO) = 5'-N-ethylcarboxamideadenosine (NECA) greater than N6-S-phenylisopropyladenosine (S-PIA) greater than 2-H-Ado greater than 2-O-Ado greater than 2-phenylaminoadenosine (CV-1808), and that for A2 receptors was 2-H-Ado greater than 2-O-Ado = NECA greater than CADO greater than CV-1808 greater than R-PIA greater than CPA greater than CHA greater than S-PIA. The Ki values of 2-H-Ado and 2-O-Ado for [3H] NECA binding to A2 receptors were 4.1 and 12.1 nM, respectively, and those for [3H]CHA binding to A1 receptors were 146 and 211 nM, respectively: the affinity of 2-H-Ado and 2-O-Ado for A2 receptors was about 36- and 17-fold higher than their affinity for A1 receptors. Injection of 2-H-Ado and 2-O-Ado (0.03-100 micrograms/kg) decreased the blood pressure of anaesthetized spontaneously hypertensive rats (SHR). A slight decrease in heart rate was observed after i.v. injection of 100 micrograms/kg 2-H-Ado and 2-O-Ado. A potent and long-lasting antihypertensive effect was also observed after oral administration of 2-H-Ado and 2-O-Ado to conscious SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1991

Attenuation of depressor response induced by platelet activating factor and acetylcholine in streptozotocin-induced diabetic rats.

The in vivo and in vitro effects of platelet-activating factor (PAF, 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphorylcholine) and acetylcholine (ACh) on vascular relaxation responses were examined in streptozotocin-induced diabetic rats. Intravenous injection of PAF and ACh (0.03 to 10 micrograms/kg) decreased the mean blood pressure in both control and diabetic rats in a dose-dependent fashion. Initial blood pressure in diabetic rats did not significantly differ from that in control rats. However, depressor responses induced by PAF and ACh in diabetic rats were attenuated more than those in control rats. In perfused mesenteric arterial bed preconstricted with methoxamine (10(-5) - 10(-4) M), PAF (10(-11) -3 x 10(-10) M) produced a concentration-dependent relaxation. However, this relaxation was significantly attenuated in the diabetic preparation compared with the control preparation. ACh also produced a concentration-dependent vasodilation in perfused mesenteric arterial bed. The concentration-response curve for the relaxation of the mesenteric arterial bed to ACh in diabetic preparation was shifted to the right compared with that in control preparation. A pretreatment with oxyhaemoglobin (10(-6) M) also shifted the concentration-response curves for relaxation to ACh in both control and diabetic preparation to the right. There was no difference in relaxation induced by sodium nitroprusside between the diabetic and the control preparation.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1991

Pharmacological profile of the 2-alkynyladenosine derivative 2-octynyladenosine (YT-146) in the cardiovascular system.

We investigated the cardiovascular effects of 2-octynyladenosine (YT-146), an adenosine A2 agonist, in various mammalian preparations in comparison with adenosine and 2-chloroadenosine. YT-146, when intravenously administered, caused a dose-dependent decrease of blood pressure in anesthetized normotensive rats (with ED30 values of 0.4 micrograms/kg), and YT-146 was 250 times more potent than adenosine. Whereas adenosine and 2-chloroadenosine decreased heart rate at approximately equihypotensive doses, YT-146 had no negative chronotropic effects at h hypotensive doses. Orally given YT-146 (0.1 - 1 mg/kg) produced a potent and long-lasting antihypertensive effect in spontaneously hypertensive rats. YT-146 was 15.9 and 12.5 times more potent than adenosine in producing relaxation of isolated porcine coronary arteries and in increasing dog coronary blood flow, respectively. Although YT-146 was equipotent to adenosine in causing a negative inotropic effect in isolated guinea pig atria, it was less potent than adenosine in producing atrioventricular conduction block in guinea pigs. On the other hand, 2-chloroadenosine was 9.1, 1.8 and 2.4 times more potent than adenosine in lowering blood pressure, relaxing isolated porcine coronary arteries and increasing dog coronary blood flow, respectively. 2-Chloroadenosine was the most potent in producing cardiodepression, i.e., negative inotropy and atrioventricular conduction block in guinea pigs. From these results, we concluded that YT-146 is a potent coronary vasodilator and also a potent, orally active and long-acting hypotensive agent having less cardiac depressant activity.

Adenosine↗
PubMed1991

Effects of chronic diabetes on vascular responses of basilar artery and aorta from rabbits with alloxan-induced diabetes.

The influences of chronically diabetic states on contraction and relaxation responses of the isolated basilar artery and aorta to various vasoactive agents were examined in alloxan-induced diabetic rabbits with 2 years duration. There were no significant differences in the reactivities of basilar artery to norepinephrine (NE), 5-hydroxytryptamine (5-HT) and KCl between age-matched control and diabetic rabbits. Maximal contractions of aorta with endothelium in response to NE and 5-HT were significantly enhanced in case concentration-response curves for NE and 5-HT-induced contractions in the aorta without endothelium from diabetic rabbits were not different from those from age-matched control rabbits. Acetylcholine-induced relaxations in both the basilar artery and aorta from diabetic rabbits were significantly attenuated compared with those from age-matched control rabbits. However, no differences were observed in concentration-response curves for sodiumnitroprusside-induced relaxations in both the basilar artery and aorta between diabetic rabbits and age-matched control rabbits. These results indicate that chronic diabetes induces an specific enhancement in the contractile responses to NE and 5-HT in aorta and an attenuation in the endothelium-dependent relaxation in both the basilar artery and aorta. These results further demonstrated that the cerebral artery is resistant to diabetes of 2 years duration as compared with the peripheral artery.

Acetylcholine↗
PubMed1990

Differences in vascular responses to vasoactive agents of basilar artery and aorta from rabbits with alloxan-induced diabetes.

Responses of the basilar artery and aorta to vasoactive agents in alloxan-induced diabetic and age-matched control rabbits were examined. There were no significant differences in the reactivity of the basilar artery to norepinephrine (NE), 5-hydroxytryptamine (5-HT), and K+ between age-matched control and diabetic rabbits. The maximal contraction of the aorta with endothelium in response to NE was significantly enhanced in the case of the aorta from diabetic rabbits. Pretreatment with 10(-6) M methylene blue or removal of the endothelium enhanced the contractile response of aorta to NE from control rabbits and, after such treatment, the concentration-response curve to NE was almost identical to that of aorta from diabetic rabbits. Basal levels of cyclic GMP but not cyclic AMP in the diabetic aorta with endothelium were significantly lower than those in the control aorta with endothelium. These results demonstrate that the cerebral artery is resistant to diabetes mellitus within 10 weeks as compared with the peripheral artery. The enhancement in the contractile response of aorta to NE in diabetic rabbits is due to the attenuation of the spontaneous release of endothelium-derived relaxing factor, through an impairment of the function of endothelial cells.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1990

Decrease in endothelium-dependent relaxation and levels of cyclic nucleotides in aorta from rabbits with alloxan-induced diabetes.

To investigate the influence of diabetes mellitus on vascular relaxation response, acetylcholine (ACh)-induced relaxation and production of cyclic GMP and cyclic AMP in aortic rings with endothelium were compared between alloxan-induced diabetic and control rabbits. ACh-induced relaxation was significantly attenuated in the aortic rings of diabetic rabbits. Concentration-response curve for ACh-induced relaxation in the aortic rings of control rabbits was shifted to the right by the pretreatment with hemoglobin, and this concentration-response curve was almost identical to that in the aorta from diabetic rabbits. Sodium nitroprusside (SNP)-induced relaxation in the aortic rings without endothelium from diabetic rabbits was similar to that in the aortic rings without endothelium from control rabbits. Basal levels of cyclic GMP and ACh-induced production of cyclic GMP were markedly lower in diabetic rabbits than those in control rabbits. On the other hand, there were no differences in basal and ACh-induced production of cyclic AMP between diabetic and control aorta. These results suggest that impairment of endothelium but not guanylate cyclase activity may be occurred in the aorta of diabetic rabbits. This impairment leads to the decrease in production of cyclic GMP through the attenuation of endothelium-derived relaxing factor (EDRF) release, and this may be responsible for the decreased endothelium-dependent relaxation of ACh.

Acetylcholine↗
PubMed1988

Effect of aspirin on haloperidol-induced cataleptic behavior in mice.

Haloperidol given intraperitoneally dose-dependently elicited cataleptic behavior, evaluated by high bar and four-cork tests, in mice. The haloperidol-induced cataleptic behavior was reduced dose-dependently after oral treatment with aspirin, a cyclooxygenase inhibitor. The intra-cerebroventricular administration of prostaglandin F2a produced cataleptic behavior of long duration determined by the high bar test. It is suggested that prostaglandins may participate in the induction of cataleptic behavior in part.

Animals↗
PubMed1987

Strain difference in an allergic asthma model in rats.

A new rat asthma model was devised, and with the model, allergic bronchoconstrictor responses and effects of disodium cromoglycate (DSCG) were compared among Wistar, Lewis and Fischer 344 rats. Rats were actively sensitized with DNP-Ascaris antigen (DNP-As) and killed Bordetella pertussis vaccine. After eight days, asthmatic response was provoked by inhalation of DNP-As. The bronchomotor response was measured with a modified Konzett-Rössler method in diaphragm-sectioned rats. The inhalation of DNP-As using a newly devised apparatus caused a marked asthmatic response with negligible effects on systemic blood pressure and heart rate. The extent of the bronchoconstriction provoked was of the following order: Wistar greater than Lewis = Fischer 344. There was no relationship between the individual 48 hr PCA titer and the bronchoconstriction that occurred in any strain of rats. The bronchoconstrictions were inhibited by DSCG (10 mg/kg, i.v.) and the inhibition ratios were 28%, 36% and 33% in Wistar, Lewis and Fischer 344 rats, respectively. The inhibitions were statistically significant in the latter two strains. Fischer 344 rats were more susceptible to the damage resulting from the operative procedures. The above findings suggest that Lewis rats are the most suitable among the above strains as a model for studying the effects of antiallergic agents.

Animals↗
PubMed1986

Possible involvement of prostaglandins in cataleptic behavior in rats.

Involvement of prostaglandin (PG) in cataleptic behavior was investigated by a high bar test method in rats. PG F2 alpha (F2a) and E2 administered intracerebroventricularly (ICV) elicited cataleptic behavior in a dose-dependent manner. The cataleptic behaviors produced by PGs were markedly inhibited by ICV pretreatment with propranolol. The cataleptic behaviors induced by haloperidol were also inhibited by propranolol. The PG F2a- and haloperidol-induced cataleptic behaviors were almost abolished by the thermal coagulation of bilateral striatum where the dopaminergic and cholinergic link is found. The pilocarpine-induced cataleptic behavior was potentiated by ICV treatment with PG F2a. On the other hand, the cataleptic behavior elicited by haloperidol was reduced after oral treatment with aspirin, a PG synthesis inhibitor. These results suggest that PGs seem to be participated in incidence of cataleptic behavior, which might involve alteration of brain beta-adrenoceptor activity.

Animals↗
PubMed1985

Synthesis and pharmacological activities of 2-alkynyl- and 2-alkenyladenine nucleosides.

A variety of 2-alkynyladenosines (2a-1) were evaluated for biological activity in antiallergic and cardiovascular tests. Compounds bearing 2-C identical to CCH(R)OH side-chain structure exhibited the most potent antiallergic activity at 0.4 mg/kg iv, in rat. These compounds, however, possessed hypotensive activity accompanied by a decrease in heart rate. Compounds substituted at the 2-position by n-pentynyl, n-hexynyl and n-octynyl showed potent hypotensive effect without showing antiallergic activity and a decrease in heart rate. Synthesis and pharmacological activities of 2-alkenyl-adenosines and 2-alkynyl-2'-deoxy- or 3'-deoxyadenosines were also described.

Adenosine↗