General Pharmacology

1. HL-004 decreased absorption of cholesteryl ester from the intestine into the lymph in a rat lymph-fistula model. 2. HL-004 reduced serum cholesterol level in acute cholesterol-fed rats. 3. HL-004 simultaneously decreased hepatic cholesteryl ester content and increased free cholesterol in cholesterol-fed rats. 4. These findings suggest that: (1) the hypocholesterolemic effect of HL-004 is principally due to inhibition of cholesterol absorption via inhibition of ACAT in the intestine; and (2) changes in hepatic cholesterol metabolism due to direct inhibition by HL-004 of hepatic ACAT may account in part for reduction of serum cholesterol level by HL-004.

1. A novel ACAT (acyl-CoA: cholesterol acyltransferase) inhibitor, HL-004, exhibited a strong inhibitory effect on the hepatic and intestinal ACAT, but was less effective on the adrenal ACAT in vitro. 2. HL-004 selectively decreased serum VLDL cholesterol, and inhibited hepatic ACAT activity in hamsters fed normal chow. 3. These results suggest that the cholesterol-lowering effect of HL-004 can be attributed to a decrease in hepatic VLDL secretion via inhibition of ACAT.

1. Several behavioral tests were used to compare the pharmacological activity of the potential antidepressant UP 614-04 with those of viloxazine and imipramine. 2. Orally-administered UP 614-04, like viloxazine, reduced locomotor activity in mice, and, like viloxazine and imipramine, it antagonized the hypothermia or ptosis induced by reserpine or tetrabenazine and the hypothermia induced by a high dose of apomorphine. 3. UP 614-04 antagonized oxotremorine-induced hypothermia, and to a lesser extent, oxotremorine-induced tremors, indicating that it possesses some CNS anticholinergic activity. 4. Both imipramine and viloxazine were more potent than UP 614-04 in potentiating yohimbine toxicity in mice. 5. Orally-administered UP 614-04 potentiated d-amphetamine-induced stereotypy to a greater extent than viloxazine, but to a lesser extent than imipramine. 6. Intraperitoneally-injected UP 614-04 was much more potent than viloxazine in increasing tryptamine convulsive potential in rats, indicating that it might exert an inhibitory action on monoamine oxidase. 7. These results indicate that UP 614-04 has a behavioral profile that is consistent with an antidepressant action, but that it differs from imipramine and viloxazine.

1. Administration of VA-045 [2-(nitrooxy)ethyl apovincaminate] and thyrotropin-releasing hormone (TRH) led to improvement in the closed head injury (CHI)-induced neuronal dysfunction such as the loss of righting reflex and disruption of spontaneous movement in rats. 2. The improvement seen with effect of VA-045, but not TRH, was abolished in rats pretreated with N-2-chloroethyl-N-ethyl-2-bromobenzylamine (DSP4), a selective noradrenaline (NA) neurotoxin. DSP4 reduced endogenous NA levels in all central nervous system (CNS) regions analyzed. 3. The extracellular concentrations of NA in the frontal cortex (FC) and in the locus coeruleus (LC) of urethane-anesthetized rats were measured using in vivo microdialysis coupled with high-performance liquid chromatography (HPLC) with electrochemical detection. VA-045 had no effect on extracellular concentrations of NA, in both FC and LC. Perfusion with clonidine, and alpha 2 adrenoceptor agonist, led to inhibition in NA output in both FC and LC, and VA-045 antagonized the effect of clonidine. 4. These findings indicate that the mode of action of VA-045 may be, at least in part, related to central NA neuronal systems.

1. We examined the alterations in cerebral free Mg2+ concentration in closed head injury (CHI) in rats and the effects of VA-045, a novel apovincaminic acid derivative, on them with in vivo 31P-NMR. 2. Free Mg2+ decreased by about 30% within 20 min after head impact and, afterward, it gradually decreased further to reach about 60% of the control level after 3 hr. VA-045 inhibited the decrease. 3. In nonimpacted rats, VA-045 did not alter the free Mg2+ level. 4. The decrease in cerebral free Mg2+ following CHI may be a critical factor in the development of irreversible tissue injury, and VA-045 may prevent it.

1. We characterized the binding sites of VA-045 [(+)-eburunamenine-14- carboxylic acid (2-nitroxyethyl)ester] in the rat brain. 2. VA-045 showed no affinity for various types of well-known neurotransmitter-related receptors or channels. However, radiolabeled VA-045 ([3H]VA-045) bound to rat brain membranes in a saturable and reversible manner. The Kd and Bmax values of [3H]VA-045 binding were 58.2 nM and 2685 fmol/mg of protein, respectively. 3. The largest specific binding of [3H]VA-045 was observed in the cerebellum, among seven brain regions, and in subcellular synaptosomes. 4. Specific binding of [3H]VA-045 was inhibited by VA-045 (Ki = 0.06 microM), a levorotatory enantiomer of VA-045 (VA-213) and its structural analog, vinpocentine. Moreover, compounds with calmodulin antagonistic activity inhibited the [3H]VA-045 binding. 5. These results suggest that VA-045 binds to specific sites, which may resemble calmodulin, on synaptic membranes in the brain.

1. The effects of VA-045, a novel apovincaminic acid derivative, vinpocetine, apovincaminic acid, brovincamine and nicergoline on peripheral and cerebral circulation were examined in anesthetized dogs. 2. Peripheral circulation: VA-045 induced a transient decrease in both blood pressure (BP) and heart rate (HR) andd an increase in vertebral arterial blood flow (VBF) without affecting femoral arterial blood flow (FBF) or carotid arterial blood flow (CBF). Vinpocetine had no effect on BP, HR, VBF, FBF or CBF. Apovincaminic acid decreased HR and increased VBF without affecting FBF, CBF or BP. Brovincamine increased VBF and decreased CBF without affecting BP or FBF. Nicergoline decrease BP without affecting VBF, FBA or CBF. 3. Cerebral circulation: VA-045 increased cerebral blood flow (CerBF) without affecting BP. Brovincamine also increased CerBF and decreased BP. The potency of VA-045 in increasing CerBF was stronger than that of brovincamine. Vinpocetine and apovincaminic acid had no effect on BP or CerBF. Nicergoline decreased BP but did not affect CerBF. 4. These findings indicate that VA-045 has a more selective vasodilative effect on the vertebral and cerebral arteries than the other reference drugs.

1. The ability of VA-045 to improve aged-related impairment on electroencephalograph (EEG), caudate spindle, performance on a passive avoidance task and cerebral blood flow (CBF) were evaluated in rats. 2. The cortical EEG of the aged rats showed a higher incidence of spontaneous spindle burst (SSB) than seen in young rats. VA-045 decreased the incidence of SSB in aged rats. In contrast, vinpocetine increased the incidence of SSB in aged rats. 3. Electrical stimulation of the striatum in aged rats lead to a higher incidence of neocortical high voltage spindle (CS) than seen in young rats. In young rats, VA-045 had no effect on the CS, whereas an age-related increase in CS was blocked by VA-045, but was enhanced by vinpocetine. 4. There were no differences in the cortical EEG arousal response elicited by stimulation of the reticular formation of the brain stem in rats of all ages. VA-045 and vinpocetine had no effect on the cortical EEG arousal response in both young and aged rats. 5. VA-045, but not vinpocetine, attenuated the age-related decreased step through latency (STL) on a passive avoidance task. VA-045 and vinpocetine did not enhance the acquisition of learning behavior in a passive avoidance task in young rats. 6. VA-045 increased the cerebral blood flow (CBF) in both young and aged rats and the potency in aged rats was greater than that in young rats. Vinpocetine had no effect on CBF in either young or aged rats. 7. The pharmacological effects of VA-045 on age-related neuronal dysfunction are discussed.

1. The influence of catechol-O-methyltransferase inhibitor U-0521 on isotonic contraction of isolated rat vas deferens was examined to determine optimal concentration and nonspecific effects. 2. Maximum responses to (-)-epinephrine were increased at 0.4 microM and 1 microM concentrations of U-0521. Epinephrine responses were progressively decreased in the presence of higher concentrations (10 microM, 30 microM and 100 microM) of U-0521. 3. The response to the nonadrenergic agonist neurokinin A was similarly depressed in the presence of 100 microM U-0521. 4. U-0521 not only inhibits COMT, at concentrations above 1 microM it nonspecifically depresses contraction of the rat vas deferens by both adrenergic and nonadrenergic agonists.

1. We examined the effects of CP-060S on cardiac function and myocardial oxygen consumption (MVO2) in anesthetized dogs. 2. CP-060S (10-300 microg/kg i.v.) decreased heart rate, increased aortic flow and decreased mean blood pressure in a dose-dependent manner. The PR interval was significantly prolonged by administration of CP-060S (300 microg/kg i.v.). 3. CP-060S (10-300 microg/kg i.v.) increased coronary blood flow in a dose-dependent manner. Left ventricular end-diastolic pressure and maximal first derivative of left ventricular pressure were not significantly affected. 4. CP-060S (10-300 microg/kg i.v.) increased coronary sinus blood flow and decreased arteriovenous oxygen difference and MVO2 in a dose-dependent manner. 5. The effects of CP-060S on cardiac function and MVO2 are qualitatively similar to those of diltiazem, a typical Ca2+ antagonist.

PY 108-068 (PY) is a potent dihydropyridine derived calcium antagonist, which is light-stable enough to allow experiments in vitro to be done under normal daylight. It potently antagonized depolarization-induced contraction of rabbit aorta (EC50: 4 X 10(-9) M) but not receptor-stimulated contraction (EC50 much greater than 10(-5) M). It also decreased the rate of spontaneously beating guinea-pig and rabbit atria very potently (EC25 2.9 and 4.3 X 10(-9) M respectively) but considerably higher concentrations were needed for negative inotropic effects on guinea-pig left atria or rabbit papillary muscles (EC25 1.5 and 1 X 10(-7) M respectively). In open chest dogs PY (10 micrograms/kg i.v.) increased coronary flow and cardiac output, lowered blood pressure, and tended to decrease heart rate while myocardial contractile force was unchanged. Myocardial oxygen consumption, however, was decreased despite the absence of cardiodepression. Similar results with respect to the systemic circulation were observed in cats. The effects of PY on the vascular beds of a large number of organs were investigated using tracer microspheres. PY effected regional vasodilatation in the heart, brain and skeletal muscle. Antivasoconstrictor effects of PY were investigated in similar cat experiments by pretreating the animals with angiotension II infusions. The vasoconstrictor effects of angiotensin II on the vessels of the kidney, stomach and small intestine were antagonized, even though no vasodilatation had been seen in these regions in the previous experiments without the vasoconstrictor pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)

1. Effects of consecutive administration of YM-09730-5, (3S)-1-benzyl-3-pyrrolidinyl-methyl (4S)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxy lat e hydrochloride, a new calcium antagonist, for 9 wk on blood pressure and urinary excretion of electrolytes were studied in stroke-prone spontaneously hypertensive (SHRSP) rats. 2. YM-09730-5 (1 and 3 mg/kg per day, p.o.) prevented development of hypertension and produced a significant reduction in blood pressure from the first week of the experiment. Nicardipine (15 mg/kg per day, p.o.) produced almost the same degree of antihypertensive effect as YM-09730-5 at a dose of 3 mg/kg. 3. YM-09730-5 produced significant diuresis and increased urinary excretion of electrolytes throughout the experiment. 4. Chronic administration of YM-09730-5 (3 mg/kg) reduced the severity of glomerular lesions in the kidney and vasculitis in the mesenteric artery. 5. These results demonstrate that YM-09730-5 is a potential antihypertensive drug with a potency about 5 times higher than that of nicardipine.

Contractile responses of the isolated bronchial preparation of guinea-pig to DMPP, a nicotinic stimulant, were inhibited by ganglion blockers but not influenced by atropine, suggesting that DMPP did not bring about a contribution by stimulation of cholinergic ganglion cells. The fact that tetrodotoxin did not influence the response to DMPP suggests that a possible site of action of DMPP is not on the nerve cells.

1. Toxicity of 1,2-dibromoethane requires bioactivation via glutathione S-transferase. Since this enzyme is undetectable in the fetus of several laboratory animal species during early gestation, in vitro studies were carried out with human fetal liver to assess potential fetotoxicity. 2. Glutathione S-transferase occurs abundantly in the human fetal liver cytosol and its titer is equal to or exceeds that found in adult human liver when estimated using 1-chloro-2,4-nitrobenzene as the second substrate. 3. Human fetal liver cytosolic glutathione S-transferase metabolized 1,2-dibromoethane with a high efficiency (mean +/- SD specific activity of 3.10 +/- 0.83 nmol/min/mg protein). This reaction was enzymatic in nature and the rate of conjugation was proportional to the concentration of reduced glutathione, 1,2-dibromoethane and the enzyme present in the reaction medium. 4. A significant bioactivation with a possibility of only limited detoxication via cytochrome P-450-dependent oxidation suggests that human fetus may be at greater risk from 1,2-dibromoethane toxicity than adult.

1. The activity of two series of imidazo[1,2-a]pyrazine derivatives on cell proliferation and differentiation and on apoptosis was examined in relation to their effects on phosphodiesterase (PDE) activity and on purinoceptors. 2. In the first series SC-18 and SC-51 inhibited mitogen-induced 3H-thymidine incorporation in human lymphocytes. 3. The compounds of the new series PAB13, PAB23 and SCA40 inhibited the proliferation of the HEL cell line. 4. Nine imidazo[1,2-a]pyrazine derivatives of the new series have been studied on the Dami cell proliferation. SCA41 and SCA44 inhibited cell growth, SCA40 and PAB40 were moderately effective, whereas PAB12 and PAB30 were devoid of effect. The antiproliferative effects of these six non-cytotoxic compounds could not be related to their action on PDE or on purinoceptors, but rather to their lipophilicity. Conversely, for PAB13, PAB15, and PAB23, the decrease in cell number was related to their cytotoxic and apoptotic effects through their cAMP-increasing and PDE-inhibitory potency, but unrelated to an effect on purinoceptors. 5. Imidazo[1,2-a]pyrazine derivatives decreased the expression of Glycoprotein (GP)Ib in Dami cells while some of them enhanced that of GPIIb/IIIa. These effects appeared to involve inhibition of both cAMP- and cGMP-PDE. 6. These studies demonstrate the potential interest of imidazo[1,2-a]pyrazine derivatives in the query of novel anticancer drugs.

1. Effects of a novel imidazoindole derivative on cholinergic function were studied in isolated tissue preparations. 2. The compound demonstrated a dose-dependent (10(-11)-10(-9) potentiation (20-60%) of acetylcholine induced tension in guinea pig ileal tissue. 3. Increases in the size of end-plate potentials and nerve evoked muscle twitches were observed in frog nerve-skeletal muscle preparations. 4. Cholinesterase activity was not inhibited. 5. The results suggest that the compound has actions at the post-synaptic muscarinic receptor complex in smooth muscle and causes pre-synaptic increases in ACh release at the neuromuscular junction.

The influence and mechanisms of action of N-ethyl- and N-benzyl-1,2-diphenylethanolamines (compounds E and B, respectively) on the arterial blood pressure and the heart rate of the rat together with their effects on CaCl2-induced arrhythmias in the rat were investigated. Both E and B in doses of (1.5-12 micromol/kg IV) decreased the arterial blood pressure and the heart rate in a dose-dependent manner. Studies with various receptor blockers, enzyme inhibitors and CaCl2 revealed that E-induced cardiovascular depressant effects were mainly due to CaCl2 channel blocking action and activation of cyclic guanylyl cyclase or release of NO whereas the cardiovascular effects of B seemed to involve both blockade of Ca2+ channels and activation of parasympathetic ganglia. Both compounds (12-14.5 micromol/kg) completely protected the rat against CaCl2 (60 mg kg(-1))-induced tachyarrhythmias. The B compound seemed to be several times more potent than the E compound in its cardiovascular depressant actions. The results suggest the potential usefulness of both compounds in the treatment of hypertension and supraventricular arrhythmias.

1. The behavioral and anticonvulsant effects of several 1, 4-benzodiazepine (BDZ) and azirino[1,2-d] [1, 4]benzodiazepine (ABDZ) derivatives were studied after intraperitoneal administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. 2. The anticonvulsant effects were evaluated on seizures evoked by means of auditory stimulation (109 dB, 12-16 kHz) in animals placed singly under a Perspex dome. 3. The 1,4-benzodiazepines were generally more potent than the related azirino[1,2-d] [1,4]benzodiazepine derivatives which, however, showed a remarkable anticonvulsant activity. The rank order of potency for anticonvulsant activity was flunitrazepam > diazepam > pinazepam > ABDZ5 > ABDZ4 > prazepam > halazepam > ABDZ1 > ABDZ3 > camazepam > ABDZ6 > ABDZ2. 4. The impairment of locomotor performance following intraperitoneal (IP) administration of the aforementioned derivatives was also evaluated by means of rotarod test. The rank order of potency for impairment of coordinated motor movements was pinazepam > flunitrazepam > diazepam > ABDZ5 > prazepam > halazepam > ABDZ4 > ABDZ3 > ABDZ1 > camazepam > ABDZ2 = ABDZ6. 5. A hypothermic activity was observed after the highest doses of the benzodiazepines studied. 6. The potency of various 1,4-benzodiazepines and azirino[1, 2-d][1,4]benzodiazepines as inhibitors of specific [3H]flumazenil binding to membranes from cerebellum or cortex was evaluated. In general, they inhibited [3H]flumazenil binding at the micromolar range. However, some ABDZ derivatives, although active as anticonvulsants, failed to displace [3H]flumazenil. 7. The azirino[1,2-d] [1,4]benzodiazepine derivatives are more lipophilic than the related benzodiazepines, but the different degree of anticonvulsant activity and impairment of coordinated motor movements cannot be directly related to the lipophilicity of the compounds studied. 8. The pharmacologic actions of ABDZ4 and ABDZ5, which appeared as the most potent anticonvulsants of the azirino[1,2-d] [1,4]benzodiazepine derivatives, were significantly reduced by treatment with flumazenil (8.24 mumol/kg IP) suggesting a clear involvement of benzodiazepine mechanisms in the anticonvulsant activity of these compounds or their metabolites. 9. The anticonvulsant activity of ABDZ4 and ABDZ5 was also evaluated against seizures induced by the two beta-carbolines, methyl beta-carboline-3-carboxylate (beta-CCM) and methyl6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), in DBA/2 mice. Both ABDZ4 and ABDZ5 gave better protection against the seizures induced by beta-CCM than DMCM, suggesting a preferential action on BDZ1 receptors.

1. The behavioural and anticonvulsant effects of eight pyrroloimidazopyridines (PI1a-d and PI2a-d) and four pyrrolopurines (PP) were studied after intraperitoneal administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. 2. The anticonvulsant effects were evaluated in DBA/2 mice on seizures evoked by means of auditory stimulation (109 dB, 12-16 kHz) in animals placed singly under a perspex dome. 3. Hypothermic activity was observed after the highest doses of the pyrroloderivatives studied. 4. Our study demonstrated that the anticonvulsant effect of pyrroloimidazopyridines (PI1-7,8,8a,9-tetrahydro-6H-pyrrolo-[1',2':1,2]imidazo[4,5-b]pyrid in-6- ones) and pyrrolopurines (PP) was generally better than corresponding pyrrolobenzimidazoles (PB) and pyrroloimidazopyridines (PI2-5,5a,6,7-tetrahydro-8H-pyrrolo[2',1':2,3]imidazo[4,5-c]pyridin-8- ones) and, in some cases, comparable to that of phenytoin and desmethylclobazam. 5. The anticonvulsant potency of the derivatives studied cannot be directly related to their lipophilicity.

1. 9-Amino-1,2,3,4-tetrahydroacridine (THA), an acetylcholinesterase inhibitor, significantly inhibited in vitro the ATP diphosphohydrolase activity of synaptosomes from the cerebral cortex and hippocampus of adult rats. 2. THA did not inhibit in vitro the 5'-nucleotidase activity of synaptosomes from cerebral cortex and hippocampus of rats. 3. THA exerted an uncompetitive inhibition on ATP diphosphohydrolase activity. This mechanism of inhibition was the same in the 2 different synaptosomal fractions (cerebral cortex and hippocampus) studied. 4. THA, proposed as a drug for the treatment of Alzheimer's disease, can alter in vitro ATP degradation in synaptosomes from the central nervous system.

1. The electrophysiological effect of 9-amino-1,2,3,4-tetrahydroacridine (THA) on the rabbit sino-atrial node was studied using double-microelectrode voltage clamp methods. 2. THA (above 10 microM) caused statistically significant decreases in the maximum rate of rise, the action potential amplitude, the rate of diastolic depolarization, and increases in the spontaneous cycle length, the action potential duration at 50% repolarization. 3. On the current systems, THA obviously depressed the time-dependent outward K+ current. The compound also decreased the slow inward Ca2+ current and the hyperpolarization-activated inward current. 4. These findings indicate that THA exerts an inhibitory action on the automaticity of sino-atrial node via effects on both outward and inward current systems.

There is now ample evidence in the literature to demonstrate the selectivity of action of DPCPX for adenosine A1 vs other adenosine receptor types in tissues derived from a wide range of species. However, care has to be exercised to ensure that its physiochemical properties do not result in the production of quantitatively misleading data. In experiments using canine tissues the still limited data available in the literature clearly and consistently demonstrate that DPCPX has a lower affinity than expected in preparations which would be anticipated to contain A1 receptors. A range of in vitro experiments also demonstrate that DPCPX is not always a "neutral" or "silent" antagonist. The mechanism underlying these additional effects is unclear, but may result from an ability of the compound to disrupt the normal interaction of the A1 receptor with Gi, or may be indicative of a lack of specificity of action. The limited evidence available suggests that the compound retains its selectivity and specificity of action in vivo, and early work indicates that the compound is proving to be a useful tool with which to explore the potential of activation of adenosine A1 receptors as an important mechanism in physiological and pathophysiological processes.

Six hours after oral administration in rat liver, diisopropyl 1,3-dithiol-2-ylidenemalonate (malotilate) decreased AMP concentrations by 60% with unchanged total adenine nucleotide concentrations and significantly increased adenylate energy charges of 0.87 in comparison to those of 0.81 in vehicle administered control animals. Twelve hours after incubation in primary cultured rat hepatocytes, malotilate decreased AMP concentrations by 18% and increased ATP and GTP concentrations by 13 and 18% respectively with significantly increased adenylate energy charges of 0.89 in comparison to 0.87 in vehicle control. Increased adenylate energy charges by malotilate coincided with the initiation of increases in protein and de novo purine synthesis in vivo, and are associated with the increased rate of de novo purine synthesis in vitro.

1. The behavioural and anticonvulsant effects of 10 1,4-benzodiazepine derivatives were studied after intraperitoneal administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. 2. The anticonvulsant effects were evaluated on seizures evoked by means of auditory stimulation (109 dB, 12-16 kHz) in animals placed singly under a perspex dome. The rank order of potency for anticonvulsant activity was alprazolam > clonazepam > flunitrazepam > diazepam > pinazepam > desmethyldiazepam > oxazepam > prazepam > halazepam > camazepam. 3. The impairment of locomotor performance following IP administration of the above reported derivatives was also evaluated by means of the rotarod test. 4. Hypothermic activity was observed after the highest doses of the benzodiazepines studied. 5. The potency of various 1,4-benzodiazepines as inhibitors of specific [3H] flumazenil binding to membranes from cerebellum or cortex was evaluated. In general, 1,4-benzodiazepines were active as anticonvulsants at micromolar range and inhibited [3H] flumazenil binding at nanomolar range. 6. The different degree of anticonvulsant activity and impairment of coordinated motor movements cannot be directly related to the benzodiazepine binding affinity or to the lipophilicity of the compounds studied.

1. The behavioural and anticonvulsant effects of several thiazolo[3,2-d][1,4]benzodiazepines (TBZ) were studied after intraperitoneal administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. 2. Anticonvulsant effects on seizures evoked by means of auditory stimulation (109 dB, 12-16 kHz) were evaluated in DBA/2 mice placed singly under a perspex dome. 3. Hypothermic activity was observed after the highest doses of the benzodiazepines studied. 4. In addition, some TBZ were examined for anticonvulsant properties with respect to clonus induced by pentylenetetrazol. 5. Our study demonstrated that some thiazolobenzodiazepine derivatives were more potent than clobazam, desmethylclobazam and chlordiazepoxide, and less potent than diazepam, desmethyldiazepam and alprazolam. 6. In the series of tricyclic benzodiazepines, thiazole nucleus fusion to the "d" edge of the 7-membered ring results in an effective increase of the energy barrier for the heptatomic system reversal, and is probably responsible for, jointly with the lack of C=N double bonds, lower activity with respect to the 1,4-benzodiazepine precursors. 7. The potency of various thiazolobenzodiazepine derivatives as inhibitors of specific [3H]flunitrazepam binding to membranes from cerebellum or hippocampus was evaluated. 8. All tested compounds produced concentration-dependent inhibition of [3H]flunitrazepam binding. 9. The pharmacological activity of TBZ2, the most active compound of this series, was significantly reduced by treatment with flumazenil (2.5 mg/kg i.p.), suggesting clear involvement of a benzodiazepine mechanism in the anticonvulsant activity of these compounds.

1. Lipid peroxidation in rat brain slices was induced by Fe+3/ascorbate. 2. Brain lipid peroxidation, as measured by malondialdehyde formation, was inhibited by all the tested nitro aryl 1,4-dihydropyridine derivatives over a wide range of concentrations. The time-course antioxidant effects of the most representative agents were assessed. On the basis of both time-course and IC50 experiments the tentative order of antioxidant activity on rat brain slices could be: nicardipine>nisoldipine> (R,S/S,R)-furnidipine > (R,R/S,S)-furnidipine>nitrendipine>nimodipine> nifedipine. 3. 1,4-Dihydropyridine derivatives that lack of a nitro group in the molecule (isradipine, amlodipine) also inhibited lipid peroxidation in rat brain slices but at higher concentrations than that of nitro-substituted derivatives. 4. All the tested nitroso aryl derivatives [2,6-dimethyl-4-(2-nitrosophenyl)-3,5-pyridinedicar. boxylic acid dimethyl ester (NTP), nitrosotoluene, nitrosobenzene] were more potent inhibitors of lipid peroxidation than were the parent nitro compounds. In conclusion, on the basis of the IC50 values determined, the rank order of antioxidant potency for these derivatives can be established as: ortho-nitrosotoluene>NTP>nitrosobenzene.

1. In rat aorta, 2,3-dibenzylbutane-1,4-diol (DBB) inhibited noradrenaline (NA)-induced contraction in a concentration-dependent manner. The inhibitory effect of DBB was observed in verapamil-pretreated muscle, and did not differ from that in the high K+ solution containing verapamil (1.0 microM). 2. DBB inhibited not only contraction, but [Ca2+]i elevation induced by NA (10 microM) with the same potency. 3. The inhibitory effect of DBB on NA-induced contraction was reversed by methylene blue (3.2 microM) and enhanced by M&B 22,948 (10 microM). 4. DBB (100 microM) alone increased cyclic GMP levels. This effect was attenuated by methylene blue (3.2 microM) and augmented by M&B 22,948 (10 microM). 5. From these results, the inhibitory effects of DBB on NA-induced contraction in rat aorta may be caused by an increase of cyclic GMP levels.

1. Inositol 1,4,5-trisphosphate (I(1,4,5)P3) releases Ca2+ from ATP-dependent Ca2+ stores in permeabilized cells and in microsomal fractions. 2. Various factors affect the amount of Ca2+ released by I(1,4,5)P3. 3. The molecular mechanism involved in the I(1,4,5)P3-induced Ca2+ release is now being investigated and I(1,4,5)P3-specific receptors and/or specific release channels are being given special attention. 4. While the I(1,4,5)P3-sensitive Ca2+ stores are presumed to locate at the endoplasmic reticulum, the relation between the I(1,4,5)P3- and the agonist-sensitive Ca2+ stores remains to be elucidated.

1.1. Ninety minutes after a single injection of clobazam (a relatively new 1,5-benzodiazepine) in varying doses (20, 30 and 50 mg/kg, s.c.), no significant change was seen in catecholamine and 5-hydroxytryptamine metabolism in brain stem of rats. However, the 50 mg/kg dose did result in a significant suppression of spontaneous locomotor activity.2.2. Furthermore, at 3 hr after clobazam injection in a dose of 50 mg/kg, there was a mar1ked increase in the level of dopamine and norepinephrine in striatum and hypothalamus, but no change in the activity of the rate-limiting enzyme, tyrosine hydroxylase, in striatum.3.3. Clobazam (50 mg/kg) at 3 hr exerted no effect on mid-brain tryptophan and tryptophan-hydroxylase, but increased the levels of 5-hydroxytryptamine and its metabolite, 5-hydroxyindoleacetic acid, in several brain regions examined.4.4. Our data seem to suggest that pharmacological action of clobazam, at least in part, is mediated via its effect upon the functioning of central monoaminergic neurons.

Selectivity of cis(-)-2,3-dihydro-3-(4-methylpiperazinylmethyl)-2-phenyl-1,5-b enzothiazepin-4 (5H)-one monohydrochloride (BTM-1086) and its butylbromide (BTM-1073) to subtypes of muscarinic receptor, M1-and M2-receptors were tested, using pirenzepine, a M1-selective antagonist and atropine, a nonselective antagonist as reference drugs. Like pirenzepine, BTM-1086 and BTM-1073 were M1-selective antagonists. BTM-1086 was most selective among the test drugs. BTM-1073, a butylbromide of BTM-1086 was more potent than BTM-1086 in antimuscarinic activity tested on the isolated ileal longitudinal muscle, suggesting that quarternarization increased selectivity to M2-receptor but not to M1-receptor.

1. The effect of KC-404, a new antiplatelet and cerebrovasodilating drug, on prostacyclin (PGI2)-induced accumulation of cyclic AMP was investigated using washed platelets of rat. 2. PGI2 enhanced the cyclic AMP content in a concentration-dependent manner. 3. KC-404 at a relatively high concentrations (above 4.34 microM) significantly increased the maximum cyclic AMP accumulation induced by PGI2, without change in its sensitivity. 4. It is concluded that KC-404 potentiates a mechanism of action of PGI2, and a possible relevance of KC-404 for the treatment of cerebrovascular disorders with a tendency of accompanying thromboembolism is suggested.

1. NC 1005 and NC 1006 (3 x 10(-6) M-10(-4) M) inhibited the contractions induced by phenylephrine (PE) and KCl in isolated rat aortas with or without endothelium. 2. In a Ca(2+)-free medium containing EGTA and nifedipine, NC 1005 and NC 1006 inhibited PE-response and a subsequent response to Ca2+ in the presence of PE. 3. NC 1005 and NC 1006 also caused relaxations of endothelium-removed aortas precontracted with PE. 4. The relaxations induced by NC 1005 and NC 1006 were potentiated by amiloride, zaprinast and theophylline but not by increasing the external Na+ concentration. 5. Methylene blue and ouabain slightly potentiated NC 1005-relaxation, but not NC 1006-relaxation. 6. Glyburide, apamine and nifedipine had no effect on the relaxations. 7. NC 1005 and NC 1006 potentiated the relaxation induced by nitroglycerin (NG) without affecting isoproterenol-relaxation. 8. In the presence of forskolin, NC 1005 and NC 1006 failed to potentiate NG-relaxation. 9. These results suggest that the vasoinhibitory effects of NC 1005 and NC 1006 may be due to an increase in the level of cAMP.

1. We compared the low molecular weight heparinoid KB-101 and heparin with regard to suppression of experimental thrombus formation and effects on bleeding time, prothrombin time (PT), and activated partial thromboplastin time (APTT) in rats. 2. KB-101 exerted a similar antithrombotic activity as that of heparin. 3. Heparin prolonged bleeding time, PT, and APTT more than KB-101 did. 4. These results suggested that KB-101 is superior to heparin as an anticoagulant.

1. We investigated the effects of short- and long-term administration of efonidipine hydrochloride (NZ-105), 1,4-dihydropyridine derivative, in conscious spontaneously hypertensive rats (SHR). 2. Oral administration of NZ-105 for 12 weeks caused diuretic and natriuretic effects, which were not attenuated during the experimental period. 3. In the short-term experiment for investigating the mechanism of the diuretic effect, intravenous injection of NZ-105 (0.03 mg/kg of body weight) significantly increased the urine volume (UV), renal plasma flow (RPF) and glomerular filtration rate (GFR). The increment rate of UV and RPF was 105.4 +/- 17.8% and 111.7 +/- 72.8%, respectively, which were larger than the increment rate of GFR (38.5 +/- 14.0%). 4. The diuretic or natriuretic effect of NZ-105 was suggested to be due to both the inhibition of sodium reabsorption and, at least in part, the increase of GFR.

1. We investigated the effect of efonidipine hydrochloride (NZ-105) against acute renal failure (ARF) in male Wistar rats. ARF was produced by ischemia or glycerol. 2. Ischemia-induced ARF was produced by right nephrectomy and clamping of the left renal artery for 60 min, followed by reperfusion. NZ-105 (20 mg/kg) was orally administered twice a day for 3 days before ARF. The plasma creatinine and urea nitrogen concentrations were markedly elevated in the ischemia ARF group on the 1st day, but the elevation was significantly suppressed by NZ-105 treatment. 3. Glycerol-induced ARF was produced by intramuscular injection of 50% (v/v) glycerol (10 ml/kg) in rats which were restricted to drinking water for 24 hr. NZ-105 (20 mg/kg) was orally administered twice a day for 3 days before ARF. NZ-105 significantly attenuated the severe impairment of creatinine and urea nitrogen clearances and the elevated fractional sodium excretion (FENa) caused by ARF. 4. In the kidney homogenate, NZ-105 (10(-6)-10(-4) M) inhibited lipid peroxidation induced by ascorbic acid and Fe or by NADPH and the inhibitory effect of NZ-105 was stronger than alpha-tocopherol, an antioxidant agent. NZ-105 (10(-5)-10(-3) M) showed radical scavenging action against diphenyl-p-picrylhydrazyl and galvinoxyl induced radicals. 5. These findings suggest that NZ-105 prevents the renal damage caused by the two kinds of ARF. Moreover, the inhibitory effects of NZ-105 against lipid peroxidation and radical formation may be one of the mechanisms involved in the prevention of ARF.

1. We investigated the renal protective effect of efonidipine hydrochloride (NZ-105) in spontaneously hypertensive rats (SHR). SHR were given a diet containing 0.075% NZ-105 from 8 weeks old for 20 weeks. 2. 24-hr urinary protein excretion in the control SHR (drug-free diet) increased with age (from 77.3 mg/kg/day at 8 weeks old to 385.4 mg/kg/day at 28 weeks old), while that in NZ-105-treated SHR was maintained at almost the same level as that in Wistar-Kyoto rats (WKY), matched control animals throughout the experimental period. 3. The histological changes of the kidney were examined by light microscopy at the end of the treatment period. In control SHR, swelling and hyalinization of glomeruli, dilatation of renal tubules containing hyaline casts and arteriolosclerosis were revealed. The long-term administration of NZ-105 markedly suppressed these changes. 4. The kidney weights and plasma creatinine concentration in control SHR were higher than those in WKY, while they were significantly reduced in NZ-105-treated SHR. The long-term administration of NZ-105 also suppressed the elevation of systolic blood pressure and the increases of plasma renin activity and aldosterone concentration. 5. These findings suggest that NZ-105 inhibits the development of proteinuria and progressive kidney damage in SHR and may become a useful antihypertensive drug with the renal protective effect.

1. Intravenous administration of NZ-105 caused a slow-onset and long-lasting hypotension in anesthetized SHR. 2. Centrally administered NZ-105 (0.04 mg/kg) slightly decreased blood pressure. 3. The hypotension of NZ-105 (0.1 mg/kg, i.v.) was not affected by atropine, propranolol, diphenhydramine plus cimetidine, aminophylline or indomethacin. 4. In ganglion-blocked rats, NZ-105 (0.003-0.3 mg/kg, i.v.) inhibited the pressor response to several hypertensive agents to a similar degree. 5. In pithed SHR, NZ-105 (0.03 mg/kg, i.v.) showed the same degree of hypotensive action as in non-treated SHR. 6. NZ-105 did not inhibit reflex responses to tilting in conscious rabbits. 7. Thus NZ-105 exerts its hypotensive action through the mechanisms of peripheral origin.

ST 1059, the pharmacologically active metabolite of midodrine, is a potent arterial and venous vasoconstrictor on isolated dog femoral vascular strips; ST 1059 is less potent than noradrenaline or norfenefrine, but more potent than etilefrine. Midodrine itself does not elicit any constrictory effects in this continuously perfused preparation. The α-adrenergic blocking agent phentolamine shifts the concentration-response curve of ST 1059 to the right. The maximum effect of very high ST 1059 concentrations is somewhat depressed.

1. The effects of bisindolylmaleimide GF 109 203X, reported to be a potent and highly selective inhibitor of protein kinase C (PKC), have been investigated on some human neutrophil functions. 2. GF 109 203X prevented O.2- production by NADPH-oxidase whatever the stimulus used for polymorphonuclear neutrophil (PMN) activation: directs PKC activators like phorbol myristate acetate (PMA) and dioctanoylglycerol, calcium ionophore (A23187), or receptor agonists like fMet-Leu-Phe (fMLP) and opsonized zymosan. 3. The effect of GF 109 203X was also examined on elastase exocytosis by neutrophils. PMA-mediated release was prevented by GF 109 203X. However, GF 109 203X had no effect on exocytosis induced by A23187 and the effect of this compound on the fMLP response changed according to its concentration. 4. These data suggest that PKC might be essential for stimulus-mediated O.2- production and also that PKC plays only a minor role in elastase secretion as compared to the role of the cytosolic calcium level.

1. Groups of lean and obese-diabetic (NIDDM) congenic male SHR/Nutl parallel-cp rats were fed a nutritionally adequate, high carbohydrate diet ad libitum with or without the alpha-glucosidase inhibitor miglitol (150 mg/kg diet) from 8 until 15 weeks of age, and key glycemic parameters were monitored throughout the study. 2. Miglitol treatment resulted in clinical improvement toward normal in percent glycosylated hemoglobin, glycemic and insulinogenic responses to an oral glucose tolerance, and in liver glucokinase activity, in concert with modest decreases in weight gain in obese rats. 3. These observations are consistent with improved insulin sensitivity in peripheral tissues following miglitol treatment, and indicate that this drug may be a useful adjunct to diet in the treatment of obesity, NIDDM, and possibly other disorders of carbohydrate metabolism.

1. Pharmacological properties of a new antitumor drug, CPT-11, were studied in some muscle preparations. 2. CPT-11 induced contraction of guinea-pig ileal and tracheal preparations, which was blocked by atropine (10(-6) M). 3. CPT-11 potentiated the contractile responses of guinea-pig ileum to acetylcholine, nicotine, serotonin and BaCl2. 4. The chronic and inotropic effects induced by isoprenaline were depressed by CPT-11. 5. These results suggest that CPT-11 has an acetylcholine action.

1. The biological activity of bradykinin (BK) and analogues containing ofr in extended N- or C-terminal portions of the molecule, as well as that of their iodinated products, was compared in isolated rat uterus and guinea pig ileum preparations. 2. BK-Tyr10 and BK-Ile10-Tyr11 were obtained by solid phase synthesis employing fmoc chemistry. 3. Iodination of BK-Ile10-Tyr11 and Tyr0-BK was performed using iodobeads, and the products were purified by reverse-phase HPLC. 4. The relative potency (RP) of noniodinated analogues in the uterus was: Tyr0-BK (1.3) = BK (1.0) > BK-Ile10-Tyr11 (0.45) > > BK-Tyr10 (0.02) and BK (1.0) > BK-Ile10-Tyr11 (0.25) = Tyr0-BK (0.22) > > > BK-Tyr10 (0.002). The RP of mono-iodo (MI) and di-iodo (DI) products was: BK (1.0) > DI-BK-Ile10-Tyr11 (0.63) = DI-Tyr0-BK (0.63) > MI-Tyr0-BK (0.46) = MI-BK-Ile10-Tyr11 (0.40). 5. The RP of noniodinated analogues in the guinea pig ileum was: BK (1.0) > MI-Tyr0-BK (0.39) > MI-BK-Ile10-Tyr11 (0.17) = DI-Tyr0-BK (0.16) = DI-BK-Ile10-Tyr11 (0.13). 6. Differences in RP of 8-10 fold for Tyr0-BK or BK-Tyr10 and 2-fold for BK-Ile10-Tyr11 were observed between the two preparations used, indicating possible receptor differences. 7. Iodination caused a reduction in the RP of the analogues in both preparations. 8. In the rat uterus, the changes in the RP of the Tyr0-BK analogues were more evident than those observed with the iodinated analogues of BK-Ile10-Tyr11, indicating that iodination causes different changes in RP, according to the localization of the Tyr in the molecule. 9. The data support the idea that iodinated analogues of BK-Ile10-Tyr11, with intact N-terminal portion, may be as useful as iodinated analogues of Tyr0-BK for the study of BK receptors.

1. Sex steroids have been shown to regulate the biosynthesis of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD). 2. In vitro studies showed that oestradiol (E2) or testosterone (T) can interfere with the bioassay of enzyme activity, but not progesterone (P4). 3. For in vivo studies, the activity of 11 beta-HSD in the testis of normal and adrenalectomized (ADX) adult male Wistar rats was determined following a daily IM injection of sex steroids for 7 days. 4. The 11 beta-HSD activity was significantly reduced (P < 0.01) either by E2 or T in normal and ADX rats. The enzyme activity in normal rats given both T and E2 was even lower (P < 0.001) than when E2 was given alone. 5. P4 given to normal and ADX rats increased the enzyme activity higher than normal (P < 0.001). 6. The presence of corticosteroids influenced the effects of E2, but not of T and P4, on 11 beta-HSD activity. 7. E2 and T downregulate 11 beta-HSD activity, whereas P4 increased it. E2 did not act through lowering T level.

1. Stereoselectivity of NC-1100 in Ca-entry blocking activity was tested in the guinea pig taenia caecum. 2. Racemic, (-)- and (+)-NC-1100 shifted the contraction-response curve of CaCl2 towards higher concentration in a parallel manner suggesting a competition. 3. (-)-NC-1100 was about 3 times as potent as (+)-NC-1100. 4. Potency of racemic NC-1100 was intermediate between those of (-)- and (+)-NC-1100.

1. With the use of the two-microelectrode voltage-clamp method, three types of voltage-activated ionic currents were examined in isolated neurons of the snail Helix pomatia: high-threshold Ca2+ current (ICa), high-threshold Ca(2+)-dependent K+ current (IK(Ca)) and high-threshold K+ current independent of Ca2+ (IK(V)). 2. The effect of bath application of the nootropics piracetam and a novel piracetam peptide analog, ethyl ester of N-phenyl-acetyl-L-prolyl-glycine (GVS-111), on these three types of voltage-activated ionic currents was studied. 3. In more than half of the tested cells, ICa was resistant to both piracetam and GVS-111. In the rest of the cells, ICa decreased 19 +/- 7% with 2 mM of piracetam and 39 +/- 14% with 2 microM of GVS-111. 4. IK(V) in almost all cells tested was resistant to piracetam at concentrations up to 2 mM. However, IK(V) in two-thirds of the cells was sensitive to GVS-111, being suppressed 49 +/- 18% with 1 microM GVS-111. 5. IK(Ca) appeared to be the most sensitive current of those studied to both piracetam and GVS-111. Piracetam at 1 mM and GVS-111 at 0.1 microM decreased the amplitude of IK(Ca) in most of the cells examined by 49 +/- 19% and 69 +/- 24%, respectively. 6. The results suggest that piracetam and GVS-111 suppression of voltage-activated calcium and potassium currents of the neuronal membrane may regulate (both up and down) Ca2+ influx into neurons.

1. Anxiety induced by forced swimming increases maximal intensity (h) of platelet aggregation (PAG) and time to reach it (t). 2. PK 11195 pretreatment (12.5 and 25 mg/kg) reverses anxiety-induced PAG changes. At 6.25 mg/kg it inhibits PAG. 3. Changes induced by anxiety on PAG may be mediated by peripheral-benzodiazepine receptors.

1. The effects S-11701 ([morpholinyl-2)-methoxy]-8-tetrahydro-1,2,3,4 quinoline) on accumulation, overflow and metabolism of [3H]norepinephrine were investigated in isolated canine saphenous veins. 2. Saphenous veins were incubated with [3H]norepinephrine in the absence or the presence of S-11701; the drug caused a concentration-dependent inhibition of the tissue content of [3H]norepinephrine and its metabolites, except for 3-methoxy-4-hydroxymandelic acid (VMA). 3. In helical strips of canine saphenous veins previously incubated with [3H]norepinephrine and then suspended for isometric tension recording and measurement of the overflow of labelled transmitter and its metabolites, S-11701 (30 microM) significantly increased the spontaneous efflux of total 3H; this effect was almost exclusively due to an augmentation of the efflux of [3H]DOPEG. 4. During electrical stimulation (9 V, 1 Hz), S-11701 at 1 microM slightly increased the overflow of extraneuronal norepinephrine metabolites without affecting the contractile response. At the higher concentration (30 microM) the compound increased the contractive response and the overflow of 3H; the latter was due mainly to an increase in [3H]DOPEG and, to a lesser extent, in [3H]norepinephrine. 5. DMI (1 microM) did not interfere with the effects of S-11701 on DOPEG efflux. 6. These experiments indicate that in the canine saphenous vein, S-11701 causes a concentration-dependent inhibition of neuronal accumulation of [3H]norepinephrine. At higher concentrations, S-11701 enters the adrenergic nerve terminals independently of the neuronal amine carrier and displaces [3H]norepinephrine from its storage sites.

1. In Ca(2+)-depleted Mn(2+)-loaded vas deferens from the guinea pig (Mn-loaded preparations), norepinephrine (NE) induced a tonic contraction dose dependently without extracellular Ca2+ and Mn2+. 2. In the beta-escin skinned vas deferens, Mn2+ as well as Ca2+ induced contractions. Guanosine triphosphate and NE increased the sensitivity of contractile mechanisms to these divalent cations. 3. Phorbol-12,13-dibutyrate (PDBu) did not induce contractions in normal (Mn(2+)-unloaded Ca(2+)-contained) preparations, whereas it induced slow sustained contractions dose dependently in Mn-loaded preparations. Although cumulative applications of PDBu desensitized the preparations to this phorbol ester, the desensitization did not affect Mn(2+)-dependent NE-induced contractions. PDBu did not affect the dose-response relation of NE in Mn-loaded preparations. 4. Staurosporine (10-100 nM) preferentially inhibited NE-induced contractions in normal and in Mn-loaded preparations to that induced by K+ in normal preparations. However, bisindolylmaleimide I (1 microM) did not inhibit NE-induced contractions in normal and Mn-loaded preparations but abolished PDBu-induced contractions. 5. These results suggest that the NE-induced increase in the Mn2+ sensitivity of contractile mechanisms contributes to Mn(2+)-dependent NE-induced contractions, which may not involve the activation of protein kinase C.

1. The beta adrenergic agonists isoproterenol and epinephrine stimulated in vitro lipolysis in adipose tissue removed from heifers 30 days pre- and 120 days postpartum. 2. Propranolol, a beta antagonist, blocked isoproterenol stimulated lipolysis pre- and postpartum. 3. Epinephrine co-incubated with propranolol resulted in a suppression of lipolysis similar to that produced by clonidine, an alpha agonist, both pre- and postpartum. 4. Bovine adipose tissue lipolysis was more responsive to isoproterenol and isoproterenol + propranolol at 120 days of lactation than 30 days prepartum. 5. Adipose tissue sensitivity to clonidine, epinephrine and epinephrine + propranolol did not differ 30 days pre- and 120 days postpartum.

1. Pharmacological properties of a new centrally acting muscle relaxant (NC-1200) were tested in isolated muscle preparations. 2. NC-1200 acted as a Ca-blocker in the guinea pig taenia caecum. The pA2-value was 5.67. 3. In the rabbit aorta, NC-1200 competed with serotonin at serotonin receptors and also shifted the concentration response curves of histamine and norepinephrine suggesting the possibility that NC-1200 interacted with histamine and norepinephrine receptors. The pA2-value of NC-1200 against serotonin was 6.02. 4. There was no evidence that NC-1200 interacted with drug-receptors in the muscles except the rabbit aorta. 5. The present results are similar to the previous findings that the properties of serotonin, histamine and norepinephrine receptors in the rabbit aorta were different from those in other muscles.