General pharmacological action of 4-(o-benzylphenoxy)-N-methylamine hydrochloride (bifemelane hydrochloride, MCI-2016)--influence on the central nervous system

General pharmacological action of 4-(o-Benzylphenoxy)-N-methylbutylamine hydrochloride (bifemelane hydrochloride, MCI-2016) was examined with regard to the effects mainly on the central nervous system. MCI-2016, at 30-100 mg/kg, p.o., only showed a weak sleep prolongation effect (mice), anti-convulsant action (mice) and a moderate facilitation of exploratory behavior, but produced no remarkable behavioral changes. Above the doses of 200 to 300 mg/kg, p.o., MCI-2016 produced a decrease in muscle or body tone, mydriasis and a slight decrease of locomotor activity. The drug, however, showed little influence on exploratory behavior, conditioned avoidance response and normal body temperature (rats). Normal body temperature in rabbits was also little affected by MCI-2016. Effects on EEG was characterized by moderate activation of spontaneous EEG and potentiation of arousal response by stimulation of the midbrain reticular formation (1.5-5 mg/kg, i.v.). The drug, however, did not significantly change the sleep-wakefulness cycle and REM-sleep in rats. MCI-2016 also showed little influence on spinal reflex potentials and neuromuscular junction at high doses (10 mg/kg, i.v.). These results may indicate that MCI-2016 has slight influence on overall behavioral and motor changes. Effects of MCI-2016 on acetic acid-induced writhing, carrageenin edema and corneal reflex were also examined. MCI-2016 showed moderate analgesic and anti-inflammatory actions at 50-100 mg/kg, p.o., and also showed local anesthetic action. The duration of local anesthetic action was relatively long but the drug produced no local damage.     

Behavioral effects of HR-592, a new derivative of indole

Effects of HR-592 on various behaviors were investigated in rats and mice. 1) HR-592 at doses of 10-100 mg/kg, p.o., and chlorpromazine at doses of 2.5-20 mg/kg, p.o., suppressed dose-dependently spontaneous activities of mice. 2) In the mice treated with HR-592, 10 and 30 mg/kg, p.o., and with chlorpromazine, 1.25-5 mg/kg, p.o., the durations of loss of the righting reflex induced by thiopental-Na were extended in a dose-dependent manner. 3) In the mice and rats when HR-592 was administered at doses of 3-100 mg/kg, p.o., catalepsy was induced in a dose-dependent manner. 4) The incidence of catalepsy induced by haloperidol in mice was reduced dose-dependently after HR-592 administration (10-100 mg/kg, p.o.). 5) Dose-dependent suppressions of the slant of screen at which the mice slipped down were observed by HR-592 at 3-100 mg/kg, p.o., and chlorpromazine at 5-20 mg/kg, p.o. 6) The rotarod performance in mice was suppressed dose-dependently by HR-592, 3-100 mg/kg, p.o., and chlorpromazine, 5-20 mg/kg, p.o. 7) HR-592 at doses of 0.3-3 mg/kg, i.p., suppressed dose-dependently the turning behavior induced by methamphetamine in unilateral substantia nigra-lesioned rats. From these results and our previous data, it is considered that HR-592 has pharmacological properties as a major tranquilizer, although its behavioral effect is slightly weaker than that of chlorpromazine. Furthermore, these results imply that HR-592 has anti-cataleptogenic activity and might thereby alleviate the adverse effect of neuroleptics such as haloperidol.     

Development of new antiepileptics. IV. Anticonvulsant activity of some derivatives of 1-(p-sulfamoyl-phenyl)-pyrrolidin-2-one (author's transl)

A series of derivatives of 1-(p-sulfamoyl-phenyl)-pyrrolidin-2-one were tested for anticonvulsant properties in rats and mice. The substance 1-(o-chloro-p-sulfamoyl-phenyl)-4-phenyl-pyrrolidin-2-one (1725) was found to have potent anticonvulsant activities in rats and mice against seizures induced by electroshock or pentylenetetrazol. The unsubstituted phenyl ring has to be in position 4, otherwise the activity of the product is weakened. The ortho position of the halogen atom on the N-phenyl is also important for the anticonvulsant effect; chlorine acts better than fluorine. The anticonvulsants tested also potentiate the sleeping time induced by pentobarbitone and attenuate the motor activity of mice. 1-(o-Chloro-p-sulfamoyl-phenyl)-4-phenyl-pyrrolidin-2-one (1725) has a LD50 of 1000 mg/kg p.o.; the lesser active substances generally have a LD50 greater than 5000 mg/kg p.o. Toxic effects of large doses were manifested by sedation and diarrhoea.     

Toxicological studies on (2'R)-4'-O-tetrahydropyranyladriamycin, a new antitumor antibiotic. Acute toxicity study in mice

A new antitumor anthracycline antibiotic; (2'R)-4'-O-tetrahydropyranyladriamycin hydrochloride (THP) was administered to ddY mice via different routes for acute toxicity studies. The LD50 values were calculated from mortality rates during a 14-day observation period, and were 14-21 mg/kg when i.v., i.p. or s.c. route was used and 420-570 mg/kg when the drug was given p.o. Upon administration of the drug, mice showed depression of spontaneous activity, anorexia, diarrhea and slight alopecia. Autopsy of the mice killed by the drug revealed atrophy of thymus, spleen, testes, uterus and ovaries, and congestion and hemorrhage in the intestines. The mice which survived through the observation period, however, showed only atrophy of thymus and sexual organs.     

General pharmacological properties of YJA 20379-1, a novel proton pump inhibitor with antiulcer activities

The general pharmacological properties of YJA 20379-1 (2-amino-4,5-dihydro-8-phenylimidazo[2,1-b]thiazolo[4,5-g]benzo thi azole), a novel proton pump inhibitor with antiulcer activities, were investigated in mice, rats, guinea pig and rabbits. YJA 20379-1 at oral doses of 50, 100 and 200 mg/kg did not affect the general behaviour, hexobarbital hypnosis, motor coordination and body temperature in mice. The drug does not have analgesic and anticonvulsant action at 200 mg/kg p.o. The locomotor activity was not affected at 100 mg/kg p.o., but at 200 mg/kg, the activity was suppressed. YJA 20379-1 (at 2 x 10(-4) g/ml) did neither produce any contraction nor relaxation of isolated organs such as rat fundus, rat uterus, guinea pig ileum and guinea pig vas deferens, and the drug did not antagonize the contractile response to several spasmogens, such as histamine, acetylcholine, serotonin and oxytocin, and the drug up to 200 mg/kg p.o. did not affect pupil size of mice. The intestinal propulsion in mice was not affected up to 200 mg/kg p.o. The gastric emptying in rats was not affected at 100 mg/kg p.o., even if retardation in gastric emptying occurred at 200 mg/kg. YJA 20379-1 did not show anti-inflammatory action nor did it affect urinary excretion up to 200 mg/kg p.o. From these results, it is suggested that YJA 20379-1 at the high dose of 100 mg/kg p.o. may not exert any adverse effects.     

General pharmacological properties of YJA20379-2, a new antiulcer agent

The general pharmacological properties of YJA20379-2 2-dimethylamino-4,5-dihydrothiazolo[4,5:3,4]pyridol[1,2-a]++ +benzoimidazole, a novel proton pump inhibitor with antiulcer activities were investigated in mice, rats, guinea pigs and rabbits. YJA20379-2 at oral doses of 50, 100 and 200 mg/kg did not affect the general behaviour, hexobarbital hypnosis and motor coordination in mice. The drug did not have analgesic or anticonvulsant action at 200 mg/kg. Locomotor activity and body temperature were not influenced at 100 mg/kg. At a concentration up to 2 x 10(-4) g/ml, YJA20379-2 did not produce any contraction or relaxation of isolated preparations, such as the rat fundus, the guinea pig ileum and the rat uterus, and did not antagonize the contractile response to several spasmogens, such as histamine, acetylcholine, serotonin and oxytocin. At dosages up to 200mg/kg p.o. YJA20379-2 did not affect the pupil size of mice. Intestinal propulsion of mice was not affected up to 200 mg/kg p.o. and the drug did not affect urinary excretion at 100 mg/kg p.o. These results indicate that at dosages up to 100 mg/kg p.o. YJA20379 was found not to affect this pharmacological profile. However, at 200 mg/kg the drug lowered body temperature and showed decreases in locomotor activity and urine volume.     

Pharmacological studies on 3-[gamma-(p-fluorobenzoyl)propyl]-2,3,4,4a,5,6-hexahydro-1-(H)-pyrazino(1,2-a)quinoline hydrochloride (compound 69/183). Part IV: other CNS effects and acute toxicity

3-[gamma-(p-Fluorobenzoyl)propyl]-2,3,4,4a,5,6-hexahydro-1-(H)-pyrazino(1,2-a)quinoline hydrochloride (centpyraquin), a potent antihypertensive and tranquillising agent, was tested for anticonvulsant, analgesic and anti-inflammatory activities in mice and for anti-emetic activity in dogs. It did not modify supramaximal electroshock seizures and failed to protect the animals against pentylenetetrazole and strychnine induced convulsions. It, however, produced some elevation in the threshold dose of strychnine. Tremorine induced tremors and salivation were not antagonised. The compound had weak analgesic activity as detected by antagonism to phenylquinone writhing and the hot plate test. It had no anti-inflammatory activity. Centpyraquin had strong anti-emetic activity against apomorphine as well as morphine. At high doses it produced fall out in the rota-rod test. The LD50 of centpyraquin in mice was 296 mg/kg i.p. and more than 1000 mg/kg p.o. and in rats it was 161 mg/kg i.p. and more than 800 mg/kg p.o. The observed CNS effects resemble those of other neuroleptics.     

Inhibition of angiotensin converting enzyme by (R)-3-[(S)-1-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetra- hydro-1,5-benzothiazepine-6-acetic acid (CV-5975), a non-sulfhydryl compound

CV-5975, (R)-3-[(S)-1-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo- 2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid, was found to inhibit rabbit lung angiotensin converting enzyme (ACE) activity with an IC50 of 3.1 x 10(-9) M and a Ki of 2.6 x 10(-9) M, inhibit the angiotensin I (A-I)-induced contraction of the guinea pig ileum with an IC50 of 1.3 x 10(-8) M, and augment the bradykinin (BK)-induced contraction of the ileum with an AC50 of 9.2 x 10(-10) M. The activity of CV-5975 was comparable to or slightly more potent than that of enalaprilat. The overall inhibition constant (Ki*), calculated from a steady-state analysis of enzyme reactions, was 4.4 x 10(-12) M for CV-5975; this indicates that the inhibition was about 5 times more potent than that of enalaprilat (2.0 x 10(-11) M). In rats, CV-5975 (0.03 and 0.3 mg/kg, i.v. and 3 and 10 mg/kg, p.o.) inhibited the A-I-induced pressor action more potently and for a longer period than did the corresponding doses of enalaprilat and enalapril. CV-5975 and enalapril (3 mg/kg, p.o.) augmented the BK-induced depressor action to a similar extent. In dogs, CV-5975 (0.3 and 1 mg/kg, p.o.) markedly inhibited the A-I-induced pressor action in a dose related manner, and the duration of this inhibitory activity was longer than with the corresponding doses of enalapril. These data provide evidence for the proposal that CV-5975 is a highly potent and long lasting ACE inhibitor.     

Effects of the new antiplatelet agent 2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo[1,5-a]pyridine on platelet aggregation and thrombosis in experimental animals.

Antiplatelet and antithrombotic effects of KC-764 (2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo[1,5-a]pyridine, CAS 94457-09-7) were studied. KC-764 inhibited arachidonic acid (AA)- and collagen-induced platelet aggregation with IC50s of 1.0 x 10(-8)-2.8 x 10(-7) mol/l for humans, rabbits, guinea pigs and dogs, and IC50s of 3.9 x 10(-6)-3.7 x 10(-5) mol/l for mice and rats in vitro. KC-764 inhibited AA- and collagen-induced aggregation with ID50s of 0.04-0.09 mg/kg p.o. in rabbits and dogs, and ID50 of 13.0 mg/kg p.o. in rats. These antiaggregatory activities of KC-764 were stronger than those of acetyl-salicylic acid (ASA), indometacin, cilostazol and ticlopidine. KC-764 inhibited the production of thromboxane B2 (TXB2) in rabbit platelet microsomes, washed platelets and reconstituted platelet rich plasma (RPRP) with IC50s of 2.9 x 10(-6) mol/l, 2.8 x 10(-7) mol/l and 4.3 x 10(-8) mol/l, respectively. The in vitro inhibitory activity of KC-764 on AA-induced platelet aggregation was more potent when RPRP was used rather than washed platelet suspension containing 30% rabbit plasma. ASA did not show such an augmentation. KC-764 prevented collagen- and AA-induced thrombosis at more than 1 mg/kg p.o. and more than 0.1 mg/kg i.v. in mice and rabbits. KC-764 showed the wider margin of dose between antiplatelet action and prolongation of bleeding time in rabbits than ASA and indometacin. These results indicated that KC-764 was a potent antithrombotic drug to prevent TXB2 production and less possible to induce untoward actions as compared with ASA or indometacin.     

Pharmacological studies of the new centrally acting muscle relaxant 4'-ethyl-2-methyl-3-pyrrolidinopropiophenone hydrochloride

The pharmacological properties of 4'-ethyl-2-methyl-3-pyrrolidinopropiophenone hydrochloride (HSR-770), a new centrally acting muscle relaxant, were investigated in experimental animals. HSR-770, within a dose range of 1-10 mg/kg i.v., relaxed alpha- and gamma-rigidities in rats, the dose required to relax gamma-rigidity being lower than the dose required to relax alpha-rigidity. When HSR-770 was intraduodenally (i.d.) administered within a dose range of 25-50 mg/kg, the relaxant activity on alpha-rigidity was potent and long-lasting in comparison with eperisone or tolperisone. HSR-770 inhibited flexor reflex more strongly than patellar reflex in a dose-dependent manner within a dose range of 2.5-10 mg/kg i.v. or 25 and 50 mg/kg i.d. in anesthetized cats. In spinal cts, HSR-770 (5 and 10 mg/kg i.v.) inhibited flexor reflex but this potency was weaker than that in anesthetized cats. HSR-770 (12.5-50 mg/kg i.d.) inhibited he crossed extensor reflex in anesthetized rats. In spinal cats, HSR-770 inhibited mono- and polysynaptic reflex potentials to the same extent and also depressed dorsal root reflex potential at 5 and 10 mg/kg i.v. HSR-770 at a dose (50 mg/kg p.o.) which exerted muscle relaxant activity on both rigidity and flexor reflex, had little effect on spontaneous motor activity (mice), hexobarbital-induced sleeping time (mice) and conditioned avoidance response (rats). These results indicate that HSR-770 is a potent centrally acting muscle relaxant and that its central nervous system depressant activity is relatively weak.     

Effects of 2-(4-methylaminobutoxy) diphenylmethane hydrochloride (MCI-2016), an omega-aminoalkoxybenzene derivative, on the gastric lesions induced by conditioned emotional stimulus

Effects of 2-(4-methylaminobutoxy) diphenylmethane hydrochloride (MCI-2016) were studied on gastric lesions induced by conditioned emotional stimulus (CES) in mice. The gastric were produced by the communication box reported by Ogawa et al. The communication box was divided into 48 compartments by transparent plastic walls. Twenty-four mice in each compartment were subjected to footshock through the grid on the floor (sender), and the other 24 mice were not (responder). The mice were subjected to CES for 12 hr. The incidences of the gastric lesions in the responder and sender groups were 72.9 and 98.8%, respectively. MCI-2016 at doses of 20-50 mg/kg (X2), p.o., reduced the incidence of gastric lesions in the responder group; and diazepam at a dose of 2 mg/kg (X2), imipramine at doses of 10 and 20 mg/g (X2), p.o., amitriptyline at doses of 5 and 10 mg/kg, (X2), p.o., and sulpiride 100 mg/kg (X2) reduced the incidences of gastric lesions in the responder group. These findings have indicated that MCI-2016 has an antiulcerative action against gastric erosion induced by CES.     

Effects of 4-(o-benzylphenoxy)-N-methylbutylamine hydrochloride (MCI-2016, bifemelane hydrochloride) on spontaneous motor activity under different experimental conditions

Effects of MCI-2016 on SMA changes were examined under several experimental conditions (normal conditions, hypoxia and head injury). Under normal conditions, MCI-2016 showed a significant increase of SMA after single administration of 12 mg/kg, i.p. Other doses (12.5-50 mg/kg, p.o. and 3-6 mg/kg, i.p.) of MCI-2016 were without significant effect. Under the same condition, MCI-2016 produced a dose-dependent increase of SMA after repeated doses of 12.5 to 50 mg/kg, p.o. (9-10 days administrations). After 5 days repeated administration, MCI-2016 significantly improved the decreased SMA due to hypoxia (rats) at 50 to 100 mg/kg, p.o. Furthermore, the drug also improved the decreased spontaneity due to head injury (mice) at 50 to 400 mg/kg, p.o. These improving effects of MCI-2016 were superior to those of Ca-hopantenate. The SMA increasing effect of MCI-2016 (12 mg/kg, i.p.) was antagonized more strongly by phenoxybenzamine than by haloperidol. In addition, the drug was shown to be rather antagonistic to the effects of anticholinergic agents. These effects may indicate the existence of qualitative differences between MCI-2016 and methamphetamine in the SMA increasing actions. It is also suggested that MCI-2016 may exhibit the above pharmacological effects through possible activation of noradrenergic and/or cholinergic mechanisms.     

Antiallergic effect of 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidaz ole difumarate (KB-2413)

Antiallergic effects of 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazol e difumarate (KB-2413) were investigated in immediate type hypersensitivities. KB-2413 (0.005-0.04 mg/kg p.o.) showed a marked inhibition on lethal anaphylaxis in guinea pigs induced by anti-egg albumin rabbit serum, and it was 30 and 1.6 times more potent than chlorpheniramine and ketotifen, respectively. KB-2413 (0.003-0.1 mg/kg p.o.) showed a dose-dependent inhibition on vascular permeability increase induced by 48 h homologous passive cutaneous anaphylaxis (PCA) and histamine in guinea pigs, being about 10-30 times and 3 times more potent than chlorpheniramine and ketotifen, respectively. All drugs did not completely inhibit 4 h heterologous PCA in guinea pigs induced by the anti-egg albumin rabbit serum in the doses used here, but KB-2413 was more effective than chlorpheniramine and ketotifen. No difference in inhibitory effect on the vascular permeability increase between the single and daily oral administration for 4 weeks of KB-2413 could be found. KB-2413, as well as chlorpheniramine and ketotifen, showed a dose-dependent inhibition on 48 h homologous PCA in rats at doses of 1-10 mg/kg p.o., and showed a concentration-dependent inhibition on Schultz-Dale reaction at 10(-8) - 10(-7) mol/l. KB-2413 (10(-5) - 10(-3) mol/l) showed a concentration-dependent inhibition of anaphylactic histamine release from isolated rat peritoneal mast cells which were passively sensitized by rat IgE. KB-2413 also inhibited compound 48/80-induced histamine release from rat peritoneal mast cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacological properties of the novel antimuscarinic agent 4-[2-(1,2-benzisoxazol-3-yl)-2-(hexahydro-1H-azepin-1-yl)a cetoxy]-1-et hyl-1- methylpiperidinium iodide

Pharmacological properties of 4-[2-(1, 2-benzisoxazol-3-yl)-2-(hexahydro-1H-azepin-1-yl)acetoxy]-1- ethyl-1- methylpiperidinium iodide (SX-810) were investigated and the following results were obtained. 1. In isolated guinea-pig ileum, SX-810 showed a competitive antagonistic effect against acetylcholine with a pA2 value of 7.93. 2. SX-810 (10-50 mg/kg p.o. or 10-50 micrograms/kg i.v.) inhibited the gastroduodenal contractions induced by bethanechol and carbachol in anaesthetized rats. 3. SX-810 (10-100 mg/kg p.o.) inhibited spontaneous gastric motility in conscious rats and rabbits. 4. SX-810 (10-100 mg/kg p.o.) inhibited gastric secretion in pylorus-ligated rats. 5. SX-810 (20-200 mg/kg p.o. or 1-10 mg/kg s.c.) inhibited the ulceration induced by pylorus ligation or by exposure to restrained and water-immersed stress in rats. 6. When administered orally to rats, SX-810 had no mydriatic effect even at 3000 mg/kg, but subcutaneously administered SX-810 (0.5-10 mg/kg) exhibited such action. 7. When administered orally to rats, SX-810 (100-500 mg/kg) caused no significant inhibition of the salivation induced by pilocarpine, but subcutaneously administered SX-810 (0.5-10 mg/kg) exhibited an inhibition of the salivation. In rabbits, SX-810 (200-500 mg/kg p.o.) also caused no significant inhibition of the salivation except at an extremely high dose of 1000 mg/kg p.o. 8. SX-810 (100-500 mg/kg p.o.) caused no significant effect on urine and electrolyte excretion in rats. These results indicate that oral use of SX-810 exhibits marked spasmolytic and antiulcerative activities without exerting systemic antimuscarinic side effects.     

Antihypertensive action of a new angiotensin converting enzyme inhibitor, (R)-3-[(S)-1-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetr ahy dro-1,5-benzothiazepine-5-acetic acid (CV-5975), in various hypertensive models

The antihypertensive activity of a new angiotensin converting enzyme (ACE) inhibitor, CV-5975, (R)-3-[(S)-1-carboxy-5-(4-piperidyl)pentyl] amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid, was examined in normotensive rats and various hypertensive animal models. In spontaneously hypertensive rats, CV-5975 (1 to 10 mg/kg, p.o.) had a dose-related, sustained antihypertensive action, which was more potent and longer than that of enalapril. The potency and duration of action of CV-5975 was intensified when it was administered repeatedly or combined with hydrochlorothiazide. CV-5975 (1 mg/kg, p.o.) inhibited the ACE activity of plasma and tissues; inhibition on the ACE activity of the aorta, kidney, and brain was marked when CV-5975 was administered repeatedly. In 2-kidney, 1 clip hypertensive rats (1 to 10 mg/kg, p.o.) and dogs (0.3 and 1 mg/kg, p.o.), CV-5975 had a marked, sustained antihypertensive action, which was more marked than that of enalapril. In normotensive rats (10 mg/kg), 1-kidney, 1 clip hypertensive rats (3 and 10 mg/kg), and hyporeninemic DOCA/salt hypertensive rats (1 to 10 mg/kg/day), CV-5975 administered orally once or repeatedly reduced blood pressure, whereas enalapril did not. These results indicate that CV-5975 is a potent and long-lasting antihypertensive agent, the action of which is mediated primarily by inhibiting ACE activity and partly by some unknown mechanisms.     

A new potent inhibitor of converting enzyme: (2R,4R)-2-(2-hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazolidinecarboxylic acid(SA446)

(2R, 4R)-2-(2-Hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazolidinecarboxylic acid (SA446) is a novel potent converting enzyme inhibitor having a sulfhydryl group in the molecule. SA446 inhibited the activity of semi-purified rabbit lung converting enzyme (IC50 = 6 nM). The contractile response of isolated guinea pig ileum to angiotensin I (AI) was markedly inhibited by SA446 (IC50 = 28 nM). On the other hand, SA446 augmented the contraction to bradykinin (BK) (AC50 = 0.7 nM), but did not affect the contraction caused by angiotensin II (AII), acetylcholine and histamine. These in vitro potencies of SA446 were 4 to 5 times larger than those of captopril. SA446 inhibited the pressor response to AI in rats (ID50 = 0.06 mg/kg, i.v., 0.48 mg/kg, p.o.) and dogs (ID50 = 0.01 mg/kg, i.v.). SA446 augmented the depressor response to BK (AD50 = 0.009 mg/kg, i.v.), but did not affect the pressor responses to AII and norepinephrine in rats. These in vivo activities of SA446 in dogs were more potent than those of captopril, but the reverse was seen in rats. Oral administration of SA446 had a hypotensive effect on two-kidney, one-clip renal hypertensive rats and spontaneously hypertensive rats, at doses over 3 and 10 mg/kg, respectively. However, the blood pressure of normotensive and DOCA-salt hypertensive rats was not affected by SA446, in doses up to 100 mg/kg. These results indicate that oral SA446 is a potent active inhibitor of converting enzyme and may be classed as an antihypertensive agent.     

General pharmacological properties of YJA20379-8, a new H+/K(+)-ATPase inhibitor with anti-ulcer activities

The general pharmacological properties of YJA20379-8 (3-butyryl-4-[(R)-1-methylbenzylamino]-8-ethoxy-1,7-naphthyridine, CAS 187654-40-6), a new H+/K(+)-ATPase inhibitor with anti-ulcer activities, were investigated in mice, rats and guinea pigs. YJA20379-8 at oral doses of 25, 50 and 100 mg/kg did not affect the locomotor activity, hexobarbital hypnosis and motor coordination in mice. The drug did not have analgesic action and anticonvulsant action at the doses of 100 mg/kg p.o. The respiration and blood pressure were not affected at 10 mg/kg i.v. in rats. YJA20379-8 at 2 x 10(-4) g/ml did neither produce any contraction nor relaxation of isolated organs, such as guinea pig ileum, rat fundus, rat uterus and guinea pig vas deferens, and the drug antagonized the contractile responses to several spasmogens, such as acetylcholine, histamine, serotonin, L-phenylephrine, oxytocin and BaCl2. The drug up to 100 mg/kg p.o. did not affect pupil size and the intestinal propulsion of mice. And it did not show an anticarrageenan action at 100 mg/kg. In this general pharmacology study, hypothermic effect in mice, retardation in gastric emptying in rats, decreases in urine excretion in rats at oral doses of 50 and 100 mg/kg of YJA20379-8 and the spasmolytic activity could be found. However, no other effects were exhibited at a high oral dose of 100 mg/kg in animals in this study.     

Syntheses and central depressant activity in mice of uracil derivatives. Studies on development of new sedative-hypnotics. II]

Fifteen kinds of uracil derivatives, which were substituted with functional groups such as benzyl (Bn), methoxymethyl (MOM), n-propyl (Pr) or allyl (A) group at the N1 and/or N3 position of uracil, were synthesized. Sedative-hypnotic activity, pentobarbital (PB)-induced sleep prolongation and acute toxicity as indices of their pharmacological activities were evaluated using mice. Spontaneous activities of mice treated with N1-benzyluracil (N1-BnU, 7), N3-benzyluracil (N3-BnU, 8), N1,N3-dibenzyluracil (DBnU, 9), N1-benzyl-N3-allyluracil (BnAU, 14) and N1-allyl-N3-benzyluracil (ABnU, 15) were measured. Ten kinds of uracil derivatives showed hypnotic activity. ED50's values of ABnU (15) and N1-propyl-N3-benzyluracil (PrBnU, 13) were 155 and 172 mg/kg, i.p., respectively. Those effects were more potent than that of barbital (179 mg/kg, i.p.) Ten kinds of uracil derivatives tested significantly prolonged the PB-induced sleeping time. N3-BnU (8) increased the spontaneous activity of mice at a dose of 80 mg/kg, i.p., while ABnU (15) depressed the spontaneous activity at a dose of 160 mg/kg, i.p. The other compounds did not show any significant effect on the spontaneous activity of mice. LD50's values of ABnU (15), PrBnU (13) and N1-methoxy-methyl-N3-benzyluracil (MOMBnU, 11) were 199, 229 and 363 mg/kg, i.p., respectively. LD50's values of the other derivatives were more than 480 mg/kg, i.p. These results indicate that the benzyl group at the N3 position of uracil is important for exhibiting sedative-hypnotic activity of uracil derivatives, and that ABnU (15) has the most potent central depressant activity among the uracil derivatives tested.     

General pharmacological studies on N-(2,6-dimethylphenyl)-8-pyrrolizidineacetamide hydrochloride hemihydrate. 1st communication: effect on the central nervous system

The pharmacological actions of N-(2,6-dimethylphenyl)-8-pyrrolizidineacetamide hydrochloride hemihydrate (SUN 1165), a new antiarrhythmic agent, on the central nervous system were studied in various experimental animals as compared with those of disopyramide, mexiletine and lidocaine, and the following results were obtained. 1. Acute toxicity of SUN 1165 in mice was similar to that of mexiletine, and twice as potent as compared with that of disopyramide and lidocaine. Main acute toxic symptoms of SUN 1165 were muscle relaxation, ataxia, clonic convulsions, tremor and a decrease in spontaneous activity in mice, rats and rabbits. In addition to these symptoms, vomiting in dogs was observed. These toxic symptoms were similar to those of lidocaine. In the case of disopyramide, ataxia, tremor and a decrease in spontaneous activity were observed in mice and rats. On the other hand, mexiletine caused central nervous excitatory symptoms, that is, tremor, Straub tail, clonic convulsions, jumping, running and opisthotonus in mice and rats, and vomiting in dogs. 2. SUN 1165 even at large doses (50-100 mg/kg p.o.) exerted no significant effects on the following changes: hexobarbital-induced induced hypnosis, oxotremorine-induced tremor, apomorphine-induced hypothermia, reserpine-induced ptosis and hypothermia, 5-hydroxytryptophan syndrome and fighting behavior in mice, and conditioned avoidance response in rats. 3. An ineffective dose of SUN 1165 (12.5 mg/kg p.o.) on spontaneous locomotor activity was lower than of disopyramide and lidocaine, however, higher than that of mexiletine. 4. SUN 1165 at large doses showed antagonistic action on toxic extensor seizures induced by maximal electroshock, picrotoxin, or strychnine in mice, but anticonvulsive effects of SUN 1165 were less potent than those of mexiletine and lidocaine. SUN 1165 had no effect on clonic convulsions induced by pentetrazol and pictrotoxin in mice, while both mexiletine and lidocaine prolonged the duration of clonic convulsions. 5. The muscle relaxant effect of SUN 1165 (50%-toxic dose, TD50 = 30 mg/kg p.o.) was more marked than that of lidocaine (TD50 = 92 mg/kg p.o.) on traction test in mice. However, effect of SUN 1165 (TD50 = 62 mg/kg p.o.) on motor incoordination was similar to that of disopyramide, mexiletine and lidocaine on the rotarod test in mice. 6. The analgesic effect of SUN 1165 was as weak as that of disopyramide, mexiletine and lidocaine on chemically and mechanically-induced pain response in mice.(ABSTRACT TRUNCATED AT 250 WORDS)     

Stimulatory effect of N-[4-[2-(dimethylamino)-ethoxy] benzyl]-3,4-dimethoxybenzamide hydrochloride (HSR-803) on normal and delayed gastrointestinal propulsion

To estimate the effect of a new gastroprokinetic agent, N-[4-[2-(dimethylamino)ethoxy]benzyl]-3,4-dimethoxybenzamide hydrochloride (HSR-803), on non-ulcer dyspepsia, the influence of HSR-803 on gastrointestinal propulsion was assayed in dogs, rats and mice in comparison with some gastroprokinetic agents. HSR-803 (30 mg/kg, p.o.) significantly enhanced gastric emptying in dogs, and it significantly improved the delayed gastric emptying induced by dopamine (0.4 mg/kg, i.p.) and morphine (1 mg/kg, s.c.) in rats. Metoclopramide (30 mg/kg, p.o.) also significantly restored the dopamine-induced delay, but at a dose of 10 mg/kg, p.o., it enhanced the morphine-induced delay in gastric emptying in rats. HSR-803 (10-100 mg/kg, p.o.) increased small intestinal transit in mice in a dose-dependent manner, and the effect was abolished by atropine (0.3 mg/kg, i.p.). Metoclopramide also increased small intestinal transit, but domperidone and cisapride had no effect. In delayed small intestinal transit in mice, HSR-803 (10-100 mg/kg, p.o.) improved the morphine (0.3 mg/kg, s.c.)-induced delay in a dose-dependent manner. In conclusion, because of the promotion of normal and delayed gastrointestinal propulsion, HSR-803 seems to be a promising gastroprokinetic agent for the treatment of non-ulcer dyspepsia. The action of HSR-803 is likely to be exerted through cholinergic stimulation.