Search

In this study, the synthesis and anticonvulsant properties of sixteen 2/3-benzoylaminopropionanilide derivatives were described. Molecular design of the compounds has been based on the modification of lacosamide which is a functionalized amino acid with a novel anticonvulsant activity. The structural confirmation of the title compounds was achieved by spectral and analytical data. The anticonvulsant activity profile of synthesized compounds was determined by maximal electroshock (MES) and subcutaneous metrazole (scMet) seizure tests, whereas their neurotoxicity was examined using rotarod test. All these tests were performed in accordance with the procedures of the Antiepileptic Drug Development (ADD) program. The majority of the compounds were effective in the MES or scMet screening tests. None of the compounds showed neurotoxicity according to the rotarod test at studied doses. Most active compounds in the series were 3, 12 and 13, which bearing 2-methyl, 2-ethyl and 2-isopropyl substituent on the N-phenyl ring, respectively., (© Georg Thieme Verlag KG Stuttgart · New York.)

A novel series of 9-alkoxy-6,7-dihydro-5H-benzo[c][1,2,4]triazolo[4,3-a]azepine derivatives was synthesized and screened for anticonvulsant activity by the maximal electroshock (MES) test and the subcutaneous pentylenetetrazol (scPTZ) test. Neurotoxic effects were also determined by the rotarod neurotoxicity test. The results revealed that all of the compounds exhibited anticonvulsant activity, Compound 5d was found to possess the most potential anticonvulsant activity in the anti-MES potency test; it had a median effective dose (ED50) of 12.3 mg/kg, a median toxicity dose (TD50) of 73.5 mg/kg, and a protective index (PI) of 6.0, which is slightly lower than the PI of the prototype drug carbamazepine (ED50=8.8, PI=8.1). In the scPTZ test, compound 5c was the most active, with an ED50 value of 19.8 mg/kg, a TD50 value of 80.8 mg/kg and a PI value of 4.1, which are much greater than the ED50 and the PI of the prototype drug carbamazepine (ED50>100, PI<0.72), Possible structure-activity relationships are also discussed., (© Georg Thieme Verlag KG Stuttgart · New York.)

A number of novel 2-(1H-imidazole-1-yl)-1-aryl-substituted ethane-1-one N-substituted phenyl(thio)semicarbazones (1-14) were synthesized to test for their anticonvulsant activity against the two seizure models, maximal electroshock (MES) and subcutaneous pentylenetetrazol (scPTZ). Title compounds were prepared by the reaction of appropriate (thio)semicarbazides with ketones. Neurotoxicity was screened by the rotarod test. The structure of compounds was confirmed by elemental analysis results and the spectroscopic techniques such as IR, 1H-NMR, 13C-NMR, ESI-MS and HRMS. As a result of activity studies, when the thiosemicarbazone compounds were compared at different doses, 2-(1H-imidazole-1-yl)-1-(2-naphthyl)ethane-1-one N-(3-chlorophenyl)thiosemicarbazone (3) and 2-(1H-imidazole-1-yl)-1-(2-biphenyl)ethane-1-one N-(4-fluorophenyl) thiosemicarbazone (12) were found selective and highly active compounds against MES-induced seizures after 0.5 h and 4 h, respectively. Beside this, 2-(1H-imidazole-1-yl)-1-(1-biphenyl)ethane-1-one N-(4-methylphenyl)thiosemicarbazone (14) was the most active compound in the scPTZ-induced seizure test after 4 h. The 2,4-dichlorophenyl (9) and 2-fluorophenyl (10) substituted biphenyl derivatives of thiosemicarbazone compounds showed neurotoxicity at higher doses.

A series of new 3-hydroxy-6-hydroxymethyl-2-substituted 4H-pyran-4-one derivatives were synthesized as potential anticonvulsant compounds. Mannich compounds were prepared by the reaction of appropriate substituted piperazine derivatives with kojic acid and formaline. The structure of the synthesized compounds was confirmed using the elementary analysis results and spectroscopic techniques such as IR, 1H-NMR and ESI-MS. Anticonvulsant activities of the synthesized compounds were examined by maximal electroshock (MES) and subcutaneous Metrazol (scMet) induced seizure tests. Neurotoxicity was determined by the rotorod toxicity test. All these tests were performed according to procedures of the Antiepileptic Drug Development (ADD) program. According to the activity studies, 2-[4-(4-chlorophenyl)piperazin-1-ylmethyl]-3-hydroxy-6-hydroxymethyl-4H-pyran-4-one (compound 11) against MES seizures and 3-hydroxy-6-hydroxymethyl-2-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]-4H-pyran-4-one (compound 7) against scMet seizures were determined to be the most active compounds at all doses without neurotoxicity.

Purpose: In an open observational prospective multicentered study on a cohort of patients with a creatinine clearance of < or = 65 ml/min and diagnosed with the "Esslinger Fall Risk Assessment" to be at an increased risk for falls the effect of daily treatment with 1 microg alfacalcidol (CAS 41294-56-8; Alpha-D3) on muscle power, balance and number of fallers and falls was investigated., Methods: In this open prospective study on 237 participants recruited in Germany, 16.9% men and 83.1% women with a mean age of 75.9 years and a mean body mass index (BMI) of 26.3 kg/m2 underwent at the beginning and after 3 and 6 months different muscle strength and balance tests such as the Timed-up and Go Test (TUG), the Tandem Stand Test (TST) and the Chair Rising Test (CRT). A successful performance in these tests has been associated with a significantly lower risk for falls and non-vertebral fractures in elderly patients (successful test performance: TUG < 12 s, TST > 10 s, CRT < 10 s)., Results: Controlled for age, gender and BMI, treatment with alfacalcidol was associated with a significantly increased performance in all three muscle and balance tests already after 3 months. This effect increased after six months of therapy and a significant increase in the number of participants who were able to successfully perform the different tests was observed: plus 74.9% for the TUG (p < .0001), plus 112% for the TST (p < .0001) and plus 108% for the CRT (p < .0001). After six months the mean time used for the TUG was decreased by 2.01 s, by 2.29 s for the CRT, and increased by 2.02 s for the TST. Controlled for age, gender, BMI and CrCI, treatment with alfacalcidol for six moths resulted in a significant 48.1% (p &#95;< or = .0001) decrease in the absolute number of fallers and a significant 51.3% (p .0001) decrease in the absolute number of falls, compared to the 6 months prior to alfacalcidol therapy., Conclusions: Treatment with alfacalcidol increases muscle power and balance as measured with three different muscle power and balance tests and leads to a highly significant decrease in the number of fallers and falls.

Safety pharmacological studies need to be performed according to ICH S7A Guidelines for finished formulations that substantially alter the pharmacokinetics and/or pharmacodynamics of the active substance in comparison to formulations previously tested (i. e. through active excipients such as penetration enhancers, liposomes, and other changes such as polymorphous system). In the present study, amorphous formulation of celecoxib (CAS 169590-42-5), a new patented formulation with altered pharmacokinetic profile was investigated in comparison with the standard crystalline celecoxib (CEL) for its undesirable pharmacodynamic effects using certain safety pharmacological studies. The effects of the new formulation on vital functions using safety pharmacology core battery like central nervous system (CNS) (functional observation battery, locomotor activity, and motor coordination) and cardiovascular system (CVS) (blood pressure, heart rate and QT interval) were investigated in laboratory rodents. In addition, supplementary safety pharmacology study on gastrointestinal system (GIT) (gastric injury potential, gastric secretion) was also carried out. Oral administration of a single dose of the amorphous celecoxib formulation (CF) varying of 50, 150 and 500 mg/kg was studied in comparison with vehicle treated control and crystalline celecoxib in animals. The maximum tolerated dose (MTD) was identified by administration of insufferable doses of amorphous formulation, extended up to 2000 mg/kg during the experiments on physiological parameters. There were no CNS and GIT safety concerns raised with respect to use of CF except the arrythmogenic risk associated with QT interval prolongation upon the high dose of CF.

Oxazepam (CAS 604-75-1) 4a served as building block in the synthesis of substituted 3-amino-1,4-benzodiazepines, which were subsequently tested in various CNS animal models. The hydroxy group of oxazepam was either activated as a chloride (Method A) or as a phosphor-oxy derivative (Method B) giving the desired 3-amino-1,4-benzodiapines 6a-6r in high yields with primary and secondary amines in a typical nucleophilic substitution reaction. Eighteen 3-substituted 1,4-benzodiazepines were prepared and served as new chemical entities and for lead structure discovery. The mixed cholecystokinin (CCK) antagonist 6e showed anxiolytic and antidepressant effects from 10 microg/kg in mice in the elevated x-maze test and the forced swimming test. The CCK1 antagonist 6 g has shown antidepressant effects from the same dose, but lacked anxiolytic properties. Both compounds potentiated at a dose of 0.5 mg/kg morphine antinociception with a maximum possible effect (MPE) about 35%. By assessing initially the MPE of antinocipection for the 18 newly synthesised benzodiazepines in the tail-flick test, 4 other benzodiazepines were found active. In further in vive evaluation the cyclohexyl derivative 6 i displayed anxiolytic, antidepressant and antinociceptive properties as single agent at a dose of 5 mg/kg without toxicity. The benzodiazepines 6i and 6p, which initially showed a higher MPE in terms of morphine potentiation (43/44%) showed analgesic effects as single agents, without having anxiolytic or antidepressant properties. The amino-piperidinyl derivative 6p displayed a similar dose-response relationship to morphine, but was 3 times more potent.

It is well known that some hydrazone derivatives of both 2-oxobenzoxazoline and 2-oxobenzothiazoline exhibit potent anticonvulsant activity. In order to investigate the effects of structural modifications on the biological properties, 14 new hydrazones of 5-chloro-2(3H)-benzox-azolinone-3-acetyl hydrazide were synthesized. The chemical structures of the synthesized compounds were established by IR, 1H-NMR spectral analyses and elementary analyses. The anticonvulsant activities of the title compounds were tested by the penthylenetetrazole induced seizure test. 5-Chloro-2(3H)-benz-oxazolinone-3-acetyl-2-(o-methoxy-benzaldehyde)-hydrazone 4d, 5-chloro-2(3H)-benzoxazolinone-3-acetyl-2-(o-methybenzaldehyde)-hydrazone 4g, 5-chloro-2(3H)-benzoxazolinone-3-acetyl-2-(p-methylbenzaldehyde)-hydrazone 4h, 5-chloro-2(3H)-benzoxazolino-ne-3-acetyl-2-(p-nitrobenzaldehyde)-hydrazone 4m, and 5-chloro-2(3H)-benzox-azolinone-3-acetyl-2-(p-dimethylaminobenzaldehyde)-hydrazone 4n were found more active than phenytoin (CAS 57-41-0) in the tests.

Background and Purpose: Many patients with chronic cerebrovascular disease complain that dizziness and depression negatively affect their daily lives. In these patients, ibudilast (CAS 50847-11-5) reportedly ameliorated dizziness. The efficacy of ibudilast was investigated and its effect on the cerebral blood flow (CBF) was recorded., Methods: The study population consisted of 11 patients (male and female) with chronic cerebrovascular disease complaining of dizziness or depression. They received 30 mg of ibudilast orally per day. The grade of vertigo and depression at entry into this study and 2 and 6 months after the start of therapy was recorded. Their depressive state was scored with the Japan Stroke Scale-Depression Scale (JSS-D) and their cerebral blood flow (CBF) was measured before and approximately 3 months after the start of ibudilast therapy., Results: At 6 months after the start of ibudilast therapy, all patients reported the resolution of dizziness; of the 6 patients with depression at entry, all experienced significant improvement. At 3 months, the CBF was significantly increased in the right frontal (p = 0.019) and occipital cortex (p = 0.004) with no significant changes in the cerebellar folia, subcortical gray matter (striatum and thalamus), and other cerebral cortices in the right cerebral hemisphere. There were no significant CBF changes in any areas of the left cerebral hemisphere., Conclusion: In patients treated with ibudilast, the amelioration of dizziness and depression was accompanied by a CBF increase in the right frontal and occipital cortices. These findings suggest that the right frontal and occipital cortices may be related to their dizziness and depression.

Bis-Mannich bases, bis(3-aryl-3-oxopropyl)ethylamine hydrochlorides 1-4, and their corresponding structural and non-classical isomers, 4-aryl-3-arylcarbonyl-1-ethyl-4-piperidinol hydrochlorides 5-8, were synthesized. The aryl part was phenyl in 1 and 5, p-methylphenyl in 2 and 6, p-chlorophenyl in 3 and 7, and 2-thienyl in 4 and 8. The chemical stuructures of the compounds were confirmed by 1H-NMR, 13C-NMR, UV, IR and elemental analyses. Anticonvulsant activities of the compounds were evaluated by the maximum electroshock (MES) and subcutaneous pentylenetetrazole (scMet) tests in the dose range of 30-300 mg/kg. Alterations in biological activity depending on modifications in chemical structure were also followed. Compounds 1-4, 6, and 8 were toxic and caused death of the animals 20 min after the injection. Compounds 2, 3 and 6 were also neurotoxic at the 100 mg/kg dose level. While only compound 7 was active in the scMet test at 300 mg/kg within 4 h, all the compounds showed activity in the MES test at different dose levels and time periods. In conclusion, compounds 5 and 7, which were not toxic and did not show neurotoxicity, seemed to be candidate compounds to develop new anticonvulsant compounds useful in the treatment of the grand mal (compounds 5, 7) and petit mal (compound 7) epilepsies.

Eighteen 1-phenyl-, 1-thiocarbamoyl- and 1-N-substitutedthiocarbamoyl-3-phenyl-5-heteroaryl-2-pyrazoline derivatives were synthesized and tested for their antidepressant and anticonvulsant activities. Their chemical structures were proved by spectral and microanalysis. The antidepressant activities of the compounds were investigated by the "forced swimming test". Results showed that compounds II-a, b, c, III-1b, 1c, 4a showed activities equivalent to or higher than pargyline hydrochloride (CAS 306-07-0) and tranylcypromine sulfate (CAS 13492-01-8) that were used as reference antidepressant drugs. Anticonvulsant activities of the compounds were determined by maximal electroshock seizure (MES), subcutaneous metrazol (ScMet.) and rotarod toxicity tests in mice according to the phase I tests of the Antiepileptic Drug Development programme. Compounds I-a, II-a, b, c, III-1b, 2a, 2c were found protective against MES and III-1b, 1c, 2a, 2c were found protective against ScMet.

In the search for new cholecystokinin (CCK) ligands, ureidopyrazolines were identified in combinatorial libraries using 168 chemically diverse amines. The structure-activity relationship optimisation of this pyrazoline template 4a resulted in novel 3-oxo-1,2-diphenyl-2,3-di-hydro-1H-pyrazol-4-yl)-N'-phenylureas 5a-5o. These novel CCK ligands have shown to act as mixed CCK-A/CCK-B ligands in a [125]I-CCK-8 receptor binding assay. The best pyrazoline 5e of this series displayed an IC50 of 20 and 25 nmol/L for the CCK-A, and CCK-B receptor, respectively. In a subsequent in vivo evaluation using various behavior pharmacological assays, an anxiolytic effect of these novel diphenylpyrazolinyl ureas was found in the elevated x-maze with an ED50 of 1.7 mg/kg. In the despair swimming test, a model for testing antidepressants, an ED50 of 0.69 mg/kg was determinated for urea 5e and the antidepressant effect had a magnitude comparable to desimipramine.

Mono-Mannich bases, 3-amino-1-aryl-1-propanone hydrochlorides (Ig1-Ig4), and their corresponding azine derivatives, N,N'-bis(3- amino-1-aryl-propylidene) hydrazine dihydrochlorides (D1-D4), were synthesized and their anticonvulsant activities were evaluated. Alterations in biological activity depending on modifications in chemical structure were also followed. The aryl part was phenyl in Ig1, D1, Ig2, D2, Ig3, D3, or p-hydroxyphenyl in Ig4, and D4. The amine part was dimethylamine in Ig1, D1, Ig4, and D4, piperidine in Ig2, D2 or morpholine in Ig3, D3. Compounds D2, D3, and D4 are new. The anticonvulsant activity was determined by maximal electroshock (MES) and subcutaneous metrazole (pentetrazol; scMet) tests. The rotorod toxicity test was used for determining neurological deficits. While the compounds were not effective in scMet, they were found to exert protective effect in MES. The results of MES are as follows: Compound [dose level (mg/kg), time (h)]: Ig1 [30 (0.5 h), 100 (0.5 h)]; Ig2 [30 (0.5 h, 4 h)]; Ig3 [30 (0.5 h), 100 (0.5 h), 300 (0.5 h, 4 h)]; Ig4 [300 (0.5 h, 4 h), 100 (4 h)]; D1 [30 (0.5 h)]; D3 [100 (0.5 h,4 h), 300 (0.5 h), 30 (4 h)]]; D4 [300 (0.5 h, 4 h)]. D2 did not show any anticonvulsant activity in both tests. Ig1, Ig2, D1, D2, and D3 exhibited neurotoxicity. Compounds Ig2, D1, and D2 were neurotoxic at 100 mg/kg dose level at 0.5 h. Ig1 was neurotoxic at 300 mg at 0.5 h, D3 was neurotoxic at 300 mg at 4 h. Conversion of mono-Mannich bases to their corresponding azine derivatives generally decreased the anticonvulsant activity. Ig3, Ig4 and D4 seem to be promising candidates to develop new anticonvulsant compounds for grand mal epilepsy for further synthesis and in vivo studies, since they were effective in MES screening and no neurotoxicity was observed with them.

The general pharmacological effects of the hexapeptide KP-102 (D-alanyl-3-(2-naphthyl)-D-alanyl-L-alanyl-L-tryptophyl-D-phenylalanyl-L-lysinamide dihydrochloride, growth hormone-releasing peptide-2, GHRP-2, pralmorelin, CAS 158861-67-7), which potently promotes growth hormone (GH) release by acting at both hypothalamic and pituitary sites, were evaluated in various animal experimental models. The administration of KP-102 showed no obvious effect at a pharmacological dose on the central nervous system. KP-102 had no significant effect on the autonomic nervous system and smooth muscle except a slight and transient increase in spontaneous motility of isolated rabbit ileum and contraction of isolated guinea pig ileum at high doses. There was negligible effect on the respiratory and cardiovascular systems, digestive system, renal function and blood system after KP-102 treatment. These results suggest that KP-102 has no serious general pharmacological effects at dose levels showing GH-releasing activity in the experimental animals. Therefore, it is concluded that KP-102 will be a useful drug for the diagnosis of serious GH deficiency and for treatment of short stature.

In this study, ten 2-acetylnaphthalene derivatives with a dioxolane structure were synthesized and screened for their anticonvulsant activities. Dioxolane derivatives were prepared by the reaction with appropriate ethanone, glycol and p-toluensulphonic acid. The structures of the compounds were elucidated by IR, 1H-NMR and elemental analysis. Anticonvulsant activities of the compounds were determined by maximal electroshock seizure (MES) test and subcutaneous metrazol (ScMet.) test. The rotarod toxicity test was used for the assessment of neurological deficits. According to the activity studies compound 6 was found neurotoxic, compounds, 1, 4, 5, 7-9 were found protective against MES and 7-10 were found protective against ScMet. Compounds 2 and 3 were found inactive.

Some acetophenone derived bis Mannich bases (B1-B5) and piperidinols (C1, C4), which are the structural isomers of B1 and B4, and also quaternary piperidine derivative C6 were synthesized and studied for anticonvulsant activity. Of the compounds, C6 was reported for the first time. Chemical structures of the compounds were confirmed by UV, IR, 1H-NMR, 13C-NMR, mass spectra and elemental analysis. Their anticonvulsant activities were determined by maximal electroshock (MES), subcutaneous metrazol (scMet) tests and rotarod test for neurological deficits. According to the activity studies, B2, B4, C1 and C4 derivatives were found to be protective against MES at 30 mg/kg and above. B1, B2, B3, B4, C4 and C6 derivatives were found to be protective against scMet. at different dose levels ranging from 30 to 300 mg/kg. Since no neurotoxicity was detected for the compounds B4 and C4, they seem to be candidate compounds for further synthesis and in vivo studies for their potential anticonvulsant activity.

In this study, some new 3-alkyl-6-arylhexahydropyrimidine-2,4-dione derivatives were synthesized as anticonvulsant agents. 6-Arylhexahydropyrimidine-2,4-diones which were used as starting materials in the synthesis of the compounds were prepared in acidic media by the cyclization of potassium cyanate and the appropriate ureido acids that were gained by the reaction of beta-aminoacids, malonic acid and ammonium acetate. The structures of the synthesized compounds were confirmed by UV, IR, 1H-NMR and elementary analysis. Their anticonvulsant activities were determined by maximal electroshock (MES), subcutaneous metrazol (scMet) and rotorod toxicity tests for neurological deficits. According to the activity studies, 3-arylalkyl-6-(p-chlorophenyl) derivatives were found to be protective against scMet, whereas 6-phenyl derivatives were not. 6-Phenyl-3-(2-morpholinoethyl)hexahydropyrimidine-2,4-dione was the only compound determined to be active against MES at 300 mg/kg dose at half an hour.

The general pharmacological properties of 2-amino-9-(3-acetoxymethyl-4-isopropoxycarbonyloxybut-1-yl)purine (CAS 247081-81-8, SK 1899), a new potential antiviral agent, were investigated in mice, rats, guinea pigs, rabbits, and dogs. The oral administration of 50, 150, and 500 mg/kg of SK 1899 had no effects on the central nervous system except that it slightly increased the spontaneous locomotor activity in mice at a dose of 500 mg/kg. SK 1899 did not disturb either the spontaneous motility or contractor-induced contraction of the isolated organs such as guinea pig ileum, rat uterus, guinea pig vas deferens, and guinea pig trachea at concentrations up to 10(-4) mol/l. It slightly increased the contractile force in the isolated guinea pig atrium at a concentration of 10(-4) mol/l. Following intravenous infusion of 5, 15, and 50 mg/kg of SK 1899 to anesthetized dogs, it did not change the mean arterial pressure, heart rate, left ventricular systolic pressure (LVSP), and respiratory rate, while it slightly increased the left ventricular positive dP/dtmax (LV + dP/dtmax) at a dose of 50 mg/kg. SK 1899 did not induce any significant changes in the intestinal charcoal meal transit in mice, basal gastric juice secretion in rats, and renal function in rats. It did not affect the blood coagulation system and phenolsulfonphthalein secretion in rats. These findings suggest that SK 1899 has a very low potential to induce any adverse pharmacological effects at the doses showing antiviral activity.

The muscarinic binding profile of a series of 2-arylpropionic acid esters on cloned human muscarinic receptor subtypes (m1-m5) was determined to investigate whether there is a correlation between pharmacological activity and muscarinic receptor subtype selectivity. Among the tested compounds, 1, 7 and 9 showed the highest affinity for the m2 and m4 receptors. Compounds 1, 7 and 9 show good affinity for m4 receptors (pKi = 7.87; 7.73 and 7.10, respectively) and are able to discriminate 10-60 fold between m4/m1, m4/m3, and m4/m5 subtypes. Conversely, these compounds are able only to weakly discriminate between m4/m2. Compounds 1 (50-300 micrograms kg-1 i.p.) and 7 (1-10 micrograms kg-1 i.p.), injected 20 min before the training session, are able to prevent the amnesia induced by dicyclomine (2 mg kg-1 i.p.) in the mouse passive-avoidance test. Compounds 1 and 7, at the highest antiamnesic doses, do not modify motor coordination and spontaneous motility as evaluated by the rota-rod test and Animex apparatus experiments.

Design, anticonvulsant properties in maximal electroshock-induced seizures [MES] and seizures induced by subcutaneous administration of pentetrazole (scPtz), and neurotoxicity of retrobenzamides (N-(nitrophenyl)benzamides and N-(aminophenyl) benzamides are reported. These data are further compared with those on carbamazepine, phenytoin, ameltolide and other reference compounds. Studies on retrobenzamides in mice dosed intraperitoneally point out a good anticonvulsant potential in the MES test for the amino derivatives (N-(aminophenyl)benzamides) and moderate activity for corresponding "nitro" derivatives. In rats dosed orally, aminoretrobenzamides were, however, less active in the MES test than in mice dosed intraperitoneally. Differences between experimental animal species and administration routes lead to hypothesize rapid metabolization of compounds, reduced intestinal resorption and increased removal from body. The presence of a methyl substitution on the N-phenyl moiety of aminoretrobenzamides attenuated these discrepancies between mice and rats. Present results indicate that pharmacological values--including the dose offering anticonvulsant protection in 50% of tested animals (ED50) and protective indices--obtained on some retrobenzamides may compete with phenytoin and carbamazepine values. By contrast with phenytoin, some retrobenzamides further exhibit activity in the scPtz test.

The competitive N-methyl-D-aspartate (NMDA) antagonist DL-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CAS 127910-31-0, 4-methyl-APPA, CGP 37849) and its ethyl ester (CAS 127910-32-1, CGP 39551) potently block NMDA-evoked whole-cell current on mouse spinal neurones in primary dissociated cell cultures with IC50 (+/- SE) values of 189 +/- 9 nmol/l (CGP 37849) and 2100 +/- 220 nmol/l (CGP 39551), respectively. The compounds dose-dependently blocked vestibular stimulation-induced convulsions in EL mice, 2 h after oral administration, with ED50 (95% CI) values of 135 (78-236) mumol/kg (CGP 37849) and 65 (45-94) mumol/kg (CGP 39551). In male Swiss albino mice, performance in the step-through passive avoidance procedure was dose-dependently impaired with ED50 (95% CI) values of 85 (56-157) mumol/kg (CGP 37849) and 27 (18-42) mumol/kg (CGP 39551). In addition performance of these animals in the rotarod test of motor coordination was impaired, 2 h after oral administration of CGP 39551, with an ED50 (95% CI) of 142 (100-201) mumol/kg. These findings demonstrate anticonvulsant activity in these potent NMDA antagonists after oral administration with CGP 39551 possessing greater relative potency. However, the unfavourable ratio of therapeutic dose versus dose inducing memory or motor impairment supports the prevailing notion that such adverse effects of the presently available compounds preclude the use of NMDA antagonists as long-term therapies.

2-Chloromethyl 3-N-substituted arylthieno (2,3-d)pyrimidin-4-ones and derivatives were synthesized by reacting 2-amino-3-carboxanilido-4,5,6,7-tetrahydrobenzo(b)thiophenes (Iabc) with chloroacetyl chloride in dioxane and by cyclizing the open chain 3-substituted carboxanilido-2-(omega-chloroacetamido)-4,5,6,7-tetrahydrobe nzo(b)thiophenes (IIabc) under acidic condition. The compounds were characterized by their spectral data and screened for central nervous system depressant activity. The compounds IIIabc and Vabc have shown marked sedative action.

The effect of a combination of 150 mg tinidazole (CAS 19387-91-8) and 1 mg oxyphenonium bromide (CAS 50-10-2), referred to as the combination, was examined in various animal species to assess its safety. In mice and rats, the combination in the dose range 30-1000 mg/kg p.o. or 250 mg/kg i.p. did not produce behavioural or neurological changes, nor did it influence pentobarbital sleeping time, though, alcohol sleeping time was altered. In anaesthetised dogs, neither blood pressure, ECG, heart rate, respiration or gastrointestinal motility was affected after single intraduodenal administration of the combination 20 and 50 mg/kg or after chronic oral administration of 25 mg/kg daily for 15 days. In isolated organs, viz. perfused rabbit heart, guinea-pig ileum and rat ileum no significant changes were observed following various doses of the combination, compared to tinidazole and oxyphenonium bromide given alone in corresponding concentrations. In conclusion, the pharmacological profile of the aforementioned combination in the dosages employed in mice, rats, guinea-pigs, rabbits and dogs shows that it is safe and well tolerated.

Levosimendan (CAS 141505-33-1) is a calcium sensitizing drug intended for the treatment of congestive heart failure. In animal experiments levosimendan has potentiated the sedative effects of ethanol. Due to poor water solubility of the compound, ethanol is used as a diluent in the intravenous formulation. In this study the possible interactions between levosimendan and ethanol in human have been studied. Twelve healthy male volunteers were included in this double-blind, randomized, cross-over study. The study consisted of three treatment periods: levosimendan 1 mg intravenously, levosimendan combined with ethanol orally and ethanol 0.8 g/kg alone. Blood samples for determination of levosimendan and ethanol concentrations were collected for 8 h after the dosing. To observe possible pharmacodynamic interactions psychomotoric tests were made before drug administration and 1h, 2h, 3h and 6h thereafter. These tests included Digit symbol substitution test, Maddox wing, Critical Flicker fusion and VAS-test for subjective assessment of performance status. Plasma levosimendan concentrations were not changed by the concomitant ethanol administration. Ethanol did not alter the pharmacokinetics of levosimendan except the volume of distribution of central compartment which was decreased. Levosimendan did neither affect elimination of ethanol. Levosimendan did not potentiate the psychomotoric effects of ethanol neither did it have any psychomotoric effects itself. In conclusion, levosimendan is not likely to have any psychomotoric adverse effects or any clinically significant interactions with ethanol.

Dextrorphan (CAS 125-73-5) is the active metabolite of the antitussive agent dextromethorphan (CAS 125-71-3). The activity of dextromethorphan, its specific pharmacology, acute toxicity and general pharmacology in respect to the central nervous system were investigated in comparison to dextromethorphan. The studies showed that dextrorphan exerts an antitussive activity comparable to the one of dextromethorphan, but a better tolerability and a lower toxicity. These results suggest to use dextrorphan instead of its precursor dextromethorphan in therapy.

The enantiomers of the anticonvulsant DL-2-hydroxy-2-phenylbutyramide (1) were prepared by resolving the (-)-quinine and (+)-1-phenylethylamine salts of the acids. The optically active acids were then esterified and reacted with ammonia to give (+)-1 and (-)-1. Optical purity of the amides was greater than 99.9% enantiomeric excess by chiral HPLC. Examination of the infrared spectra of the enantiomers and the racemate of 1 in chloroform solution showed identical spectra, but the spectrum of the racemate in a KBr disc was somewhat different from those of the pure enantiomers. Pharmacologically, 1 and its enantiomers have a similar significant anticonvulsant activity at peak drug effect against pentylenetetrazol seizures, but a variation in time between the enantiomers was found with the anticonvulsant activity. In the rotarod ataxia test (-)-1-possessed the lowest neurotoxicity.

Various combinations of carbamazepine (CAS 298-46-4), felbamate (CAS 25451-15-4), and phenytoin (CAS 57-41-0) were evaluated in mice (i.p.) for anticonvulsant activity (maximal electroshock seizure test) and minimal neurotoxicity (rotarod test). The results obtained from these studies were analyzed using response surface methodologies (RSM). The outcomes of these analyses in regard to anticonvulsant activity suggest that, under these experimental study conditions, at 0.5 h post treatment there is a significant carbamazepine/phenytoin synergism even though none of the drugs has a significant dose-response by that time when given alone, and that at 1.0 h post treatment, the combination dose-response is additive. Thus, there appears to be an important dose/time relationship. In regard to the neurotoxic response, the results suggest a significant carbamazepine/phenytoin synergism at 0.25 h post treatment and an additive neurotoxic effect due to the combination of felbamate/carbamazepine/phenytoin at 0.5, 1.0 and 2.0 h post exposure.

The putative cognition enhancer linopirdine (3,3-bis(4-pyrindinylmethyl)-1-phenylindolin-2-one, CAS 105431-72-9) is supposed to act by enhancing the release of neurotransmitters, especially acetylcholine. The present study assessed the effects of a single administration of this compound on the central nervous system in eight different rat and mouse models (CNS general pharmacology). In each test performed, linopirdine was administered subcutaneously in doses of 3, 10, and 30 mg/kg. The compound did not affect traction ability and nociceptive responsiveness nor did it induce catalepsy. Linopirdine impaired motor coordination in the balance rod test. The compound showed a distinct proconvulsive action in the pentylenetetrazole threshold dose test and induced in the highest dose tested (30 mg/kg) lethal seizures in some mice. It increased the duration of hexobarbital-induced anaesthesia in mice. Rats treated with linopirdine showed ptosis, salivation, slight sedation, paw beating and slight hypothermia. These results support the hypothesis that linopirdine acts by elevating the release of different neurotransmitters such as acetylcholine and dopamine. The compound has a low potential to produce side effects at pharmacodynamic active doses.

2-Amino-5-tert-butyl-2-oxazoline (ATBO, 2) was synthetized from 3,3-dimethyl-2-iodobutyl isocyanate via N-(3,3-dimethyl-2-iodobutyl) urea (1). The structures of compounds 1 and 2 are based on analytical and spectroscopic data. Compound 2 induced in rats and mice a peripheral antinociceptive effect through both spinal and supraspinal mechanisms. ATBO did not impair motor coordination or activity of the experimental animals.

Some new N-arylazole acetamide derivatives have been prepared by the reaction of alpha-bromo-N-arylacetamide with imidazole, pyrazole and 1,2,4-triazole. The structures of these compounds have been confirmed by UV, IR, 1H-NMR and elementary analysis. Their anticonvulsant activities were determined by maximal electroshock (MES) and subcutaneous metrazol (Scmet) tests. Most of the compounds showed anticonvulsant activity with significantly low neurotoxicity according to Phase I tests. Compound 6 carrying alpha-naphthyl and 1,2,4-triazole was found active in the MES test with ED50 = 64.9 mg/kg and TD50 = 221.0 mg/kg but it was not active in corneally stimulated rats. Antibacterial and antifungal activities of the compounds were determined against S. aureus, E. coli, P. aeruginosa, C. albicans, C. parapsilosis, C. pseudotropicalis and C. stellatoidea by using the microdilution broth method. Compounds 8 and 10 showed significant activity (MIC < 32 micrograms/ml) against various Candida species.

The newly synthesized compound, 1-amino-5-bromouracil (ABU, CAS 127984-93-4), showed unique anxiolytic activity in rats and mice. Its minimum effective dose was 10 mg/kg p.o. in the Geller type conflict test in rats, and it showed anxiolytic activity at a dose of 20 mg/kg i.p. in the Vogel type conflict test in mice. ABU also induced loss of the righting reflex in mice. The ED50, a dose level that induces loss of the righting reflex in 50% of mice, was 86.4 mg/kg p.o. On the other hand, ABU showed only weak activities both potentiating the drug-induced anesthesia and myorelaxing in comparison with diazepam. Furthermore ABU did not show an affinity for benzodiazepine receptor. Thus, the pharmacological profile of ABU is concluded to be different from that of diazepam.

The pharmacological effects of the novel fluoroquinolone 7-(1R,4R-2,5-diazebicyclo[2.2.1]heptan-2-yl)-1-(1,1-dimethyl )ethyl-6-fluoro - 4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (BMY-40062, CAS 116143-32-9) on central nervous system were investigated in mice and rats, in comparison in some cases with those of reference quinolones. BMY-40062 showed no effect on general behavior, spontaneous activity, body temperature and neuromuscular coordination in rats at the doses of 1000 and 250 mg/kg. None of the quinolones tested including BMY-40062 modified the seizures induced by bicuculline, a specific GABA A antagonist. BMY-40062 and ciprofloxacin did not consistently influence the pentetrazol-induced convulsions. On the contrary, pefloxacin exhibited a marked convulsivant activity. In the fenbufen (non-steroidal anti-inflammatory drug)-induced seizure model, BMY-40062 showed no effect. Enoxacin, norfloxacin followed by ciprofloxacin elicited a convulsivant effect in presence of fenbufen. Under these experimental conditions, BMY-40062 had no effect on the central nervous system compared to the other tested quinolones in rodents.

Pergolide (LY127809, CAS 66104-23-2), a non-selective dopamine agonist, was evaluated for broad behavioral properties in a wide range of pharmacological tests. The selective dopamine2(D2) agonist, bromocriptine, served as a reference standard for those tests where behavioral activity was noted with pergolide. Pergolide and bromocriptine were administered orally to mice at doses of 0.3-30 and 3-300 mg/kg, respectively. Both compounds produced biphasic effects on spontaneous activity, increased hexobarbital-induced sleep time, and lowered mouse body temperature. Qualitative changes with pergolide were observed with some mice showing hyporeactiveness, ptosis, slowed respiration and placing loss. Reserpine-induced hypothermia was reversed by pergolide with significant increases in the body temperature of reserpine-treated mice. However, a further reduction in the body temperature of reserpinized hypothermic mice was seen following bromocriptine administration. Acetic acid-induced writhing and performance on the rotarod were both impaired by higher doses of pergolide. Bromocriptine administration also reduced writhing at higher doses but did not alter performance on the rotarod. Pergolide had no effect on seizure activity as evaluated by electroshock, pentylenetetrazol (pentetrazol) or strychnine. Oxotremorine-induced tremors and salivation, grip strength, and tail-flick were not affected by pergolide. Neither pergolide nor bromocriptine altered established shuttle-avoidance behavior in rats at oral doses of 0.1 to 30 mg/kg. Behavioral assessment of pergolide in dogs was complicated by severe emetic responses at clinically relevant doses greater than 0.003 mg/kg. In summary, these data suggest that pergolide produces a behavioral profile which is characteristic of dopaminergics.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of benazepril hydrochloride (CGS 14824 A, CAS 86541-74-4), a novel angiotension I converting enzyme inhibitor, on the central nervous systems, were studied in experimental animals. Benazepril hydrochloride (3 or 10 mg/kg/d, p.o. for 14 days) dose-dependently inhibited the increase in the blood pressure caused by continuous norepinephrine (NE) infusion in spontaneously hypertensive rats (SHR) and suppressed in seizures induced by a monoamine oxidase inhibitor, tranylcypromine in NE infused SHR. Benazepril hydrochloride transiently increased spontaneous motor activity in mice, tended to inhibit acetic acid-induced writhing in mice and decreased fast wave sleep and slow wave deep sleep on EEG in cats at a high dose of 100 mg/kg p.o. However, benazepril hydrochloride at the same dose showed no effect on other central nervous and sensory systems in experimental animals.

The anticonvulsant activity of a homologous series of phenyl alcohol amides is described. (+-)-2-Hydroxy-2-phenylbutyramide (1), (+-)-3-hydroxy-3-phenylpentanamide (2) and (+-)-4-hydroxy-4-phenylhexanamide (3) were prepared and tested for their anticonvulsant profile and neurotoxicity. 1, 2 and 3 exhibited a broad profile of anticonvulsant activity and a similar significant activity in the seizures provoked by maximal electroshock, pentetrazol, 4-aminopyridine, bicuculline and thiosemicarbazide, but in the strychnine and picrotoxin tests, the protection was variable. The rotarod ataxia test was used to evaluate their neurotoxicity. In this test 2 possesses the lowest neurotoxicity.

Effects of recombinant human Tumor Necrosis Factor (rHu-TNF, PT-050) administered s.c. and i.v. on the central nervous system were investigated behaviorally and physiologically in different animal species. With i.v. administration at doses of 10(4) U/kg and less, PT-050 produced no significant changes in most of behavioral and physiological tests, except that a transient increase in rectal temperature in dogs occurred with 0.765 x 10(4) U/kg and acetic acid-induced writhing syndrome in mice was inhibited with 10(4) U/kg. Locomotor activity in mice was inhibited after 3 x 10(4) U/kg. With 10(5) U/kg and more, in addition to the above effects, diverse effects were observed as follows: various symptoms were induced in general behavior in mice such as piloerection, catalepsy, lowering of body position, ptosis and pupil dilatation; rectal temperature was increased in rats and decreased in mice; cortical EEG was synchronized in hippocampal theta waves were disturbed in gallamine-immobilized cats. On the other hand, with s.c. administration, the effect on rectal temperature was seen at 10(4) U/kg in dogs and at 10(5) U/kg in rats. Cortical EEG in conscious rabbits was affected with 10(6) U/kg. At higher dose of 10(7) U/kg. PT-050 (s.c.) further influenced locomotor activity, rectal temperature and acetic acid-induced writhing syndrome in mice. However, even with 10(7) U/kg (s.c.), no effect was found in general behavior, rotarod performance and hexobarbital narcosis in mice. Thus, it is concluded that PT-050 has weaker effects on the central nervous system by s.c. route than by i.v. route. From the present findings and the efficacy of PT-050 as TNF, it is suggested that PT-050, when administered intratumorally, may be useful for cancer therapy without severe side effects.

Female albino rats were treated with sodium salicylate dissolved in tap water orally by intubation. The first group received daily doses of 25, 75 or 150 mg/kg from day 15 through day 20 of pregnancy. The second group received daily doses of 4.2, 12.5 or 25 mg/kg on day 20 and on day 21, i.e. the day of parturition. Administration of the intermediate and high doses caused a marked increase in the mortality rates of the young animals. However, the development of the surviving young rats was similar to the controls and no change in behaviour was noted.

7-Chloro-1-(2,2,2-trifluoroethyl)-5-(o-fluorophenyl)-1,3-dihydro-2H-1, 4-benzodiazepine-2-thione (Sch 16134, quazepam) is a new hypnotic drug with demonstrated clinical efficacy. Quazepam has been shown in our laboratories to have potent hypnotic activity and fewer side effects at effective doses than flurazepam, which was studied concurrently. Hypnotic potency was estimated in mice via antagonism of electroshock-induced convulsions (ECS), potentiation of hexobarbital-induced sleeping time, and chlorprothixene potentiation. The respective oral ED50's (95% fiducial limits) in the 3 tests were 0.9 (0.4-2.0), 0.5 (0.3-0.8) and 0.05 (0.02-0.08) mg/kg for quazepam and 1.6 (1.1-2.3), 0.6 (0.4-1.0) and 0.11 (0.07-0.42) mg/kg for flurazepam. The duration of action of quazepam as measured by antagonism of ECS in mice was similar to that of flurazepam at equi-effective doses but quazepam had a faster onset. When potential tolerance to hypnotic efficacy was studied, quazepam did not show tolerance after dosing 20 mg/kg p.o. twice daily (b.i.d.) for 5 days, whereas tolerance was seen with flurazepam at equi-effective doses b.i.d. for 5 days. In conscious, unrestrained squirrel monkeys and cats, quazepam produced sedation with less ataxia and less evidence of CNS stimulant action than flurazepam. On the basis of the aforementioned studies, quazepam should be an effective hypnotic with less potential for ataxia, paradoxical excitation, and tolerance than flurazepam.

The drug solvents glycerin, N-(beta-hydroxyethyl)-lactamide, and polyethylene glycol 400 (Lutrol 9) were examined for their pharmacodynamic properties in the following tests: i.p. toxicity, "sign pattern", inclined screen test, balance rod test, and potentiation of hexobarbitone sleeping time in mice, spasmolytic activity in the guinea pig isolated ileum, and cardiovascular studies in anaesthetized rats, cats, and dogs including the i.v. toxicity. In mice and rats glycerin exhibited the highest tocicity as well as the greatest activity in potentiating hexobarbitone sleeping time. In the isolated ileum the solvents showed unspecific spasmolytic activities with histamine, carbachol, and BaCl2 as spasmogens. After i.v. administration in rats, cats, and dogs the solvents caused cardiovascular effects even in very low doses. Based on the pharmacodynamic properties, doses are recommended for each solvent which should not be exceeded without control experiments in the laboratory routine. These tolerable doses do not only depend on the species but also on the test concerned.

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.

An equilibriometric study has been performed on 20 healthy young women before and after the intake of 7 times 100 mg minocycline during 3 days. A systematic neurootological equilibriometry was performed analyzing the vestibular ocular, the vestibular spinal, the retino-ocular and the spontaneous nystagmus pathways. The results demonstrate that the tetracycline minocycline provokes a ponto-medullary liberation of the central vestibular regulating mechanisms. The central vestibular disinhibition could be exhibited by the monaurally elicited vestibular ocular nystagmus as well as by the radar image like cranio-corpography recordings of the head and body movements during a vestibular spinal stepping test. In parallel with these findings the participants of the study increasingly complained about vertigo of the rocking type, instability, malaise and wretching. Thus, the untoward side effects of a tetracycline like minocycline which is a frequent complaint of the patients, appears to be due to a central disinhibition of the vestibular equilibrium regulating mechanisms.

2-Amino-2-oxazolines are heterocyclic compounds with interesting pharmacological properties. Several derivatives of this chemical series were studied in psychopharmacological tests. One derivative 4,5-dihydro-5-[methyl(4-phenyl-1-piperazinyl)]-2-oxazolamine (COR 32-24), had an antidepressant profile. Its structure can be compared to trazodone in its phenylpiperazine group and to toloxatone in its oxazoline group. This molecule antagonized reserpine-induced hypothermia and ptosis, oxotremorine-induced hypothermia and high-dose apomorphine-induced hypothermia. It also potentiated yohimbine-induced sublethality and decreased the immobility of forced swimming. It had no monoamine oxidase inhibitory activity. These results suggest a profile close to that of viloxazine and to that of a classic antidepressant.

The effects of detomidine (4-[(2,3-dimethylphenyl)methyl]-1H-imidazole, Domosedan) and its congeners, MPV compounds, are evaluated in the cardiovascular system and related to their sedative action using clonidine and xylazine for reference purposes. The structure of the MPV compounds had been modified with methyl substituents in the phenyl ring, with differing lengths in the alkyl bridge, and with variations in the imidazole terminus. The lipophilicity of the test compounds had been estimated in terms of apparent partition coefficients in the octanol/buffer (pH 7.4, 24-26 degrees C) using the HPLC technique. The lipophilicity of the MPV compounds was found to be higher than for either clonidine or xylazine, suggesting a more rapid penetration into the central nervous system. Some of these 21 MPV compounds were hypotensive and bradycardic in anaesthetized rats. Interestingly a number of these MPV compounds were only bradycardic but not clearly hypotensive after i.v. administration to anaesthetized rats, this being most obvious in the case of the 2,5-dimethylphenyl derivative MPV 867. A further characteristic distinguishing between the central and peripheral alpha-adrenoceptors regulating cardiovascular tone was a distinct inability of some derivatives active at peripheral cardiac presynaptic (pithed rats) and central (young chicks) alpha 2-adrenoceptors to reduce blood pressure in anaesthetized rats. The sedative action of the compounds after i.m. injection into 2- to 5-day-old chicks was in general related to their central hypotensive and bradycardic effect in anaesthetized rats, and with peripheral vasopressor and sympatho-inhibitory activity in pithed rats.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacology of hydrated 1 less than ([5-(3,4-dichlorophenyl)-2-furanyl]methylene) amino greater than-2,4,-imidazolidinedione sodium salt (clodanolene sodium), as skeletal-muscle contraction antagonist, is presented. Clodanolene sodium is remarkable in that it has no measurable direct effect on the peripheral or central nervous systmes. Skeletal muscle relaxation can be achieved with this drug at doses that do not affect motor coordination. Rats receiving clodanolene sodium for up to 30 days evidenced a downward trend in gross observation score of skeletal muscle relaxation, but the extent of twitch inhibition was the same on day 30 as on day 1. In an animal model of muscle spasticity (Straub-tail mouse), clodanolene sodium has been shown to be more efficacious for induction of skeletal muscle relaxation than neuromuscular blocking agents, local anesthetics, or centrally-acting muscle relaxants. Clodanolene sodium's mode of action has been identified as specific for skeletal muscle. It has no measurable effect on neuromuscular transmission or on the electrically excitable surface membrane. Indirect evidence indicates that the site of action of clodanolene sodium, like that of dantrolene sodium, is within the muscle cell and is related to caffeine-sensitive calcium stores. Its skeletal-muscle relaxant activity, we suggest results from a decrease in the release of calcium from the sarcoplasmic reticulum.

Neuro- and psychopharmacological effects of isopropyl-(2-methoxy-ethyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (Bay e 9736, nimodipine) are described using a variety of methods measuring behavior under normal conditions, under the influence of psychotropic drugs, as well as under the influence of ischemia or hypoxia. It has been demonstrated that nimodipine -- although not being very potent when measured in mg/kg -- exerts neuro- and psychopharmacological effects characterized by influences on the extrapyramidal system, aggressive defensive behavior, and chemically induced seizures. Electroencephalographical changes become evident whenever the normal equilibrium between cerebral catecholamine and cerebral serotonin levels is disturbed. When measured under the contingencies of a one trial passive avoidance paradigm, nimodipine is able to prevent the occurrence of retrograde amnesia in rodents after amnesiogenic events such as maximal electroconvulsive seizure or hypoxia. The substance prevents behavioral and electroencephalographic disturbances, elicited by a total cerebral ischemia, which is lethal in non-treated cats. It is concluded that nimodipine besides being a cerebrally vasoactive agent has psychopharmacological properties with a profile of actions hitherto unknown.

Pharmacological effects of o-chloro-alpha-[(tert.-butylamino)methyl]benzylalcohol hydrochloride (C-78) on the nervous systems and miscellaneous organs were studied. 1. Through a low dosage of C-78 had little influence on the central nervous system, a high dosage of C-78 had a little slow-waving effect on the spontaneous EEG in rabbits, inhibitory action of the convulsion caused by pentetrazol or electroshock in mice and anti-pyrogenic action in rabbits. C-78 also dose-dependently inhibited the increase of motility caused by amphetamine in mice. 2. Only high concentrations of C78 had a local anesthetic action on the cornea and the skin of the back in guinea pigs. 3. C-78 significantly increased non-esterified fatty acids (NEFA) and glucose contents of blood in rabbits, but these actions were inhibited by propranolol. Another, high dosage of C-78 had anti-ulcer and anti-inflammatory action. From the results of the previous experiments and this study, it was concluded that C-78 is a new beta 2-receptor stimulating drug where beta 2-receptor selectivity is greater than that of isoproterenol, salbutamol and clorprenaline.

4-Amino-6-methoxy-1-phenyl-pyridazinium methyl sulfate (ameziniummetilsulfate, LU 1631, Regulton), in this study briefly called amezinium, was tested for possible central effects taking particular account of the mechanisms of action found for this substance in other studies. 1. The most conspicuous action of amezinium was in modifying reserpine-induced ptosis and reserpine-induced hypothermia. When amezinium is given before reserpine, the ED50 values are 0.15 and 3.9 mg/kg p.o. for both mouse and rat. These effects can be explained by a peripheral site of action since peripheral sympathomimetic effects can also be demonstrated in this dose range. Higher doses (10 mg/kg and upwards p.o.) were required to abolish reserpine-induced hypothermia 17 h after reserpine administration, an effect which probably requires a central site of action. But for imipramine, desipramine and pargyline the effective doses are the same in both experimental models (administration before and after reserpine, respectively). 2. Amezinium potentiated the effect of a threshold dose of L-dopa. Based on the central symptoms, higher doses (10 mg/kg p.o.) were also required for this effect. 3. With blood pressure increasing doses, the sleeping-waking pattern was modified in that duration and number of REM-episodes were reduced; in cats there was no parallel increase of wakefulness whilst in rats there was a slight relative increase of wakefulness. 4. Amezinium, particularly at high doses (46.4 mg/kg and upwards), exhibited a central depressant effect on the spontaneous behaviour of mice and rats and on orientational hyperactivity of mice. Based on the modification of aggregation toxicity, the effect of methamphetamine was reduced. In no dose range was there any evidence of methamphetamine-like effects (increase of motor activity, inhibition of food intake and increase of aggregation toxicity). 5. Amezinium did not affect the duration of hexobarbital anaesthesia or the coordination of mice on a rotating rod. 6. The acute toxicity of amezinium in mice and rats was low. The oral LD50 for mice was 1630 mg/kg and for rats 1410 mg/kg.

These experiments were carried out to supplement the pharmacodynamic profile of 2[1-(2,6-dichlorophenoxy)-ethyl]-2-imidazoline hydrochloride (lofexidine, Lofetensin and Loxacor), a potent hypotensive imidazoline derivative with a central mode of action. Effects indicative of a central sedative action were seen in various experiments on mice and rats. However, comparative studies with clonidine, particularly those involving the interaction with hexobarbital, the effect on motor coordination on a rotating rod, the effect on body temperature and other experiments, indicated that lofexidine had a 10 to 100 fold less sedative effect than clonidine, depending on the test and the route of administration. In rats there was a dose-related, diuretic and saluretic effect. This effect was not seen in dogs. In rabbits and guinea pigs, lofexidine exhibited local anaesthetic effects and its potency and duration of action were comparable to those of the reference compounds (tetracaine or mepivacaine). Lofexidine did not modify gastric secretion in rats. On the other hand, it inhibited chemically induced (phenylbutazone) and stress-induced (swimming) gastric ulcer formation in rats. Antiinflammatory and analgesic activities in rats and mice were, at most, very weak. Lofexidine increased blood glucose levels of normoglycaemic rats; clonidine is known to have the same effect. In order to investigate the possibility of combining lofexidine with a diuretic drug for the treatment of hypertension, the interaction with hydrochlorothiazide was studied in some experiments. The results obtained from these experiments showed that there was no adverse effect and the diuretic and saluretic effects of hydrochlorothiazide were not impaired. No findings militated against the use of lofexidine as an antihypertensive drug. It is likely that lofexidine, in contrast to clonidine, has less marked central sedative effects.

The pharmacological properties of a new type of anti-cancer agent, 1-(2-tetrahydrofuryl)-5-fluorouracil (FT) and uracil (U), in a molar ratio of 1:4, were investigated and compared with those of FT, 5-fluorouracil (5-FU) and uracil. UFT at doses larger than 874.8 (FT: 270.0) mg/kg p.o. produced slight central nervous depression in mice and rats, as demonstrated by prolongation of the thiopental anesthesia, analgesic activity in the acetic acid stretching test, an anticonvulsant effect on maximal electroshock convulsions and decrease in body temperature. In rabbits UFT at a dose of 291.6 (FT: 90.0) mg/kg p.o. produced an increase in the drowsy EEG pattern. UFT at high dose produced clonic convulsions in mice and rats and cardiac fibrillation in rabbits. UFT had slight cardiorespiratory effects in anesthetized rabbits and dogs and at a dose of 291.6 (FT: 90.0) mg/kg i.v. it increased the voltage of the T-wave in ECG in anesthetized dogs. At high doses UFT inhibited gastrointestinal transit in mice and it caused emesis in dogs. At doses larger than 291.6 (FT: 90.0) mg/kg p.o. it had a diuretic effect and at higher doses it slightly increased the blood glucose level in rats. FT at equal doses to UFT had the same effects as UFT and the effect of 5-FU was similar to that of UFT. The pharmacological activity of uracil was much less potent. It was concluded that the pharmacological effect of UFT was almost entirely due to FT, however, UFT had much less effect than FT in inducing clonic convulsions, increasing the voltage of the T-waves in ECG and inducing emesis, its depressant effect is probably due to its constituent uracil.