Enhancement of ambulation-increasing effect of methamphetamine by peripherally-administered 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (R-THBP) in mice

Behavioral effects of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (R-THBP), a co-factor for tyrosine hydroxylase and tryptophan hydroxylase, were investigated by means of ambulatory activity in mice. Single administration of R-THBP (50 and 100 mg/kg, s.c.) showed no significant effect on the mouse's ambulatory activity for 5 hr. The ambulation-increasing effect of methamphetamine (2 mg/kg, s.c.) was dramatically enhanced and prolonged by the pretreatment with R-THBP (100 mg/kg, s.c.) 0, 2, 6, 12 and 24 hr before, but not 18 or 36 hr before, the methamphetamine administration. However, when combined administration of R-THBP (100 mg/kg, s.c., 2 hr before) with methamphetamine (2 mg/kg, s.c.) was repeated at intervals of 3-4 days, the enhancement by R-THBP of the methamphetamine effect was observed only in the 1st and 2nd administration, but not in the later administration. The pretreatment with R-THBP (100 mg/kg, s.c., 2 hr before) enhanced the ambulation-increasing effect of ephedrine (80 mg/kg, i.p.), but failed to modify those of cocaine (20 mg/kg, s.c.), mazindol (2.5 mg/kg, s.c.), bromocriptine (8 mg/kg, i.p.), morphine (20 mg/kg, s.c.) and scopolamine (0.5 mg/kg, s.c.). It is noteworthy that R-THBP differentially modifies the ambulation-increasing effect of the above-mentioned drugs.     

Salicylate protects against MPTP-induced impairments in dopaminergic neurotransmission at the striatal and nigral level in mice

The analgesic and anti-inflammatory drug sodium salicylate was studied for its potential protective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. C 57BL/6 mice were treated with a single dose of sodium salicylate (50 mg/kg or 100 mg/kg i.p.) or saline immediately before injection of MPTP (30 mg/kg or 40 mg/kg s.c.) or saline. Analysis of striatal dopamine and metabolites as well as immunostaining for tyrosine hydroxylase of nigral sections was performed 7 days after MPTP treatment. MPTP (30 mg/kg) led to a strong decrease in striatal dopamine levels (1.87+/-0.27 ng/mg) compared to saline-treated controls (15.72+/-0.78 ng/mg), which was significantly attenuated by sodium salicylate 50 mg/kg and 100 mg/kg (5.59+/-0.56 ng/mg and 8.64+/-0.89 ng/mg, respectively). Remarkably, the MPTP-induced loss of tyrosine hydroxylase immunoreactivity in nigral cell bodies was nearly completely prevented by the higher dose of sodium salicylate. Furthermore, salicylate demonstrated radical scavenging effects in an in vitro Fenton system indicated by HPLC determination of the dihydroxylated reaction products of salicylate, namely, 2,3- and 2,5-dihydroxybenzoic acid. The protective effects of salicylate against reversible or irreversible impairments in dopaminergic neurotransmission after MPTP treatment may be related to its radical scavenging properties and other mechanisms which need to be clarified.     

Effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on striatal tyrosine hydroxylase and tryptophan hydroxylase in rat

The results reported here indicate that treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused significant changes in the dopamine-synthesizing enzyme, tyrosine hydroxylase. The authors examined the effects of two doses of MPTP on the activities of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) in the striatum, and also the time-course of these effects. Rats received an intraperitoneal loading dose, followed by a 24-hr infusion of MPTP (total doses of 21 or 42 mg) from subcutaneously-implanted osmotic pumps. Seven days after treatment, the activity of tyrosine hydroxylase was decreased by MPTP (42 mg); however, the activity of tryptophan hydroxylase was not affected. In time-course experiments, the activity of tyrosine hydroxylase was maximally reduced at 3 and 7 days after treatment with MPTP (42 mg). The activity of tryptophan hydroxylase did not significantly change at any time-point. Concurrent administration of haloperidol (HALO; 2 mg/kg, 4 doses) with MPTP significantly enhanced the depression of the activity of tyrosine hydroxylase in the striatum caused by MPTP, while treatment with haloperidol alone had no such effect. Concentrations of dopamine in the striatum were maximally decreased to approx. 50% of control in animals treated with haloperidol and MPTP (42 mg), whereas treatment with MPTP alone decreased concentrations of dopamine to approx. 70% of control.     

Comparison of the chronic and acute effects of D-lysergic acid diethylamide (LSD) treatment on rat brain serotonin and norepinephrine

The effects of repeated administration of small doses of l-lysergic acid diethylamide (LSD) on brainstem norepinephrine (NE), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), tyrosine, tryptophan, tyrosine hydroxylase and tryptophan hydroxylase have been studied in male Sprague-Dawley rats. A daily dose of 20 μm/kg given for 14 days resulted in a significantly lowered NE level and tyrosine hydroxylase activity measured 24 hr after the last injection. Treatment with 100 ifμm/kg/day for the same period of time produced similar changes together with a significantly lower brainstem tyrosine content. Evidence was obtained that the NE turnover in rat brainstem was significantly increased at the higher dose level only. The lower dose of 20 μm/kg/day also resulted in an elevated 5-HT and lowered 5-HIAA content. However, when the dose was increased to 100 μm/kg/day the 5-HT content was unchanged and the 5-HIAA content increased. The 5-HT turnover was reduced when the rats were treated with 20 μm/kg/day but significantly elevated when the 100-μm dose was used.     

Pharmacological study of nicergoline. (I): Protective effect against anoxic brain damages in animals

The protective effects of nicergoline (NCG) against anoxic brain damages in animals were compared with those of dihydroergotoxine (DHE) and phentolamine (PTA). NCG (16 mg/kg, i.p.) prolonged the survival time of mice under hypobaric hypoxia, but DHE and PTA shortened the time. NCG (1-16 mg/kg, i.p. and 16-64 mg/kg, p.o.), like DHE, dose-dependently prolonged the survival time of mice after a lethal dose of KCN (3 mg/kg, i.v.), but PTA did not. NCG (8-128 micrograms/kg, i.v.), like DHE, dose-dependently protected against disappearance of EEG of rats in histotoxic anoxia induced by a sublethal dose of KCN (1.5 mg/kg, i.v.), but PTA did not. Its protective effect was 10 times or more stronger than that of DHE. NCG (1-16 mg/kg, i.p.) dose-dependently promoted recovery from behavioral disorders and disturbance of cerebral energy metabolism of mice in histotoxic anoxia induced by a sublethal dose of KCN (1.8 mg/kg, i.v.). NCG (100 microM), like DHE, showed antagonistic action against inhibition of cerebral cytochrome oxidase activity by KCN, but PTA did not. The ED50 values of NCG, DHE and PTA for the protective effect against adrenaline-induced death in mice were 1.18, 0.27 and 0.35 mg/kg (i.p.), respectively. 7) These results suggest that NCG may show protective effects against the anoxic brain damages due to its ameliorating action on cerebral energy metabolism, mainly contributed by an activation of cerebral cytochrome oxidase, without relation to its alpha-blocking action.     

Preclinical toxicity and pharmacokinetics of the Bruton's tyrosine kinase-targeting anti-leukemic drug candidate, alpha-cyano-beta-hydroxy-beta-methyl-N- (2,5-dibromophenyl) propenamide (LFM-A13)

The leflunomide (CAS 75706-12-6) metabolite (LFM) analog alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)-propenamide (LFM-A13, DDE-28, CAS 244240-24-2) is a rationally-designed specific inhibitor of the TEC family protein tyrosine kinase, Bruton's tyrosine kinase (BTK). LFM-A13 exhibited favorable pharmacokinetics in CD-1 mice, BALB/c mice, rats, and dogs. The intraperitoneal bioavailability was estimated to be -100%, while the oral bioavailability was -30%. LFM-A13 enters, but does not bind to multiple tissues followed by a rapid elimination from most of the tissues. Limited distribution of LFM-A13 to extravascular tissues and its corresponding low volume of distribution could be attributed to its plasma protein binding. LFM-A13 was not toxic to mice, rats, or dogs at daily dose levels as high as 100 mg/kg. LFM-A13 formulated as a suspension and hard gelatin capsules for oral administration showed a rapid absorption and favorable pharmacokinetic features. These preclinical research studies provide the basis for future pre-IND studies and clinicaldevelopment of LFM-A13 as an intravenously or orally administered new anti-leukemia agent targeting BTK.     

Pharmacological study of TJ-8007 (Tsumura-Zokumeito) (I): Protective effects of TJ-8007 against anoxic brain damage

The protective effects of TJ-8007 (Tsumura-Zokumeito, Traditional chinese medicine) against cerebral anoxia were investigated with various experimental models in mice and rats. 1) In histotoxic anoxia, TJ-8007 (0.3-3.0 g/kg, p.o.) dose-dependently demonstrated a protective effect on coma induced by a sublethal dose of KCN (1.8 mg/kg, i.v.) in mice. Ifenprodil (30 mg/kg, p.o.) tended to reduce the coma time, but papaverine (100 mg/kg, p.o.) showed a negative effect. 2) TJ-8007 (0.3-3.0 g/kg, p.o.) dose-dependently tended to prolong the survival time of mice subjected to a lethal dose of KCN (3.0 mg/kg, i.v.), TJ-8007 also improved the survival rate at the dose of 3.0 g/kg. Ifenprodil (30 mg/kg, p.o.) or papaverine (100 mg/kg, p.o.) exerted a similar effect on the survival time, but did not affect the mortality. 3) In the normobaric hypoxia with a gas mixture of 96% N2 and 4% O2, TJ-8007 (0.3-3.0 g/kg, p.o.) did not affect the survival time of mice. On the other hand, papaverine (100 mg/kg, p.o.) prolonged the survival time, and phenytoin (100 mg/kg, p.o.) showed a marked protective effect, but ifenprodil (30 mg/kg, p.o.) produced an adverse effect. 4) In the asphyxic anoxia induced by stopping artificial respiration of immovable rats, TJ-8007 (1.0, 3.0 g/kg, p.o.) showed a protective effect on the fall of systemic blood pressure and on the decline of heart rate; furthermore, it dose-dependently prolonged the disappearance time of cortical activity. Also, phenytoin (100 mg/kg, p.o.) tended to protect against the fall of blood pressure and prolonged the cortical resistance time.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increase in rat regional brain cyclic nucleotides by thyrotropin-releasing hormone (TRH) and its analog DN-1417

The effects of thyrotropin-releasing hormone (TRH) and its analog gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate (DN-1417) on adenosine 3',5'-monophosphate (cyclic AMP) and guanosine 3',5'-monophosphate (cyclic GMP) levels in rat brain were investigated using a radioimmunoassay method. The time course of elevation of these nucleotides in various brain regions after administration of DN-1417 showed a peak at 5 to 15 min followed by a gradual decrease. DN-1417 (1 to 10 mg/kg i.p.) caused a dose-related increase in cyclic AMP levels in the cerebellum, cerebral cortex, striatum, nucleus accumbens, thalamus, hypothalamus and brain stem; whereas significant increases in cyclic GMP were observed in the cerebellum, nucleus accumbens and brain stem. TRH (3 to 10 mg/kg i.p.) caused significant increases of cyclic AMP in the cerebellum, cerebral cortex, nucleus accumbens, thalamus and brain stem and also caused an increase in cerebellar cyclic GMP. With one exception, DN-1417, apomorphine (Apo), methamphetamine (MAP) (all, 3 mg/kg i.p.)- and TRH (10 mg/kg i.p.)-induced increases in cyclic nucleotides were blocked by pimozide (1 mg/kg i.p., 4 hr before), a dopamine receptor blocker; the exception was a TRH-induced increase in cerebellar cyclic GMP. These increases were not blocked by propranolol (10 mg/kg i.p., 30 min before), an adrenergic beta-receptor blocker. alpha-Methyl-p-tyrosine (alpha-MT, 250 mg/kg i.p., 4 hr before), a tyrosine hydroxylase inhibitor, almost completely blocked DN-1417- and MAP-induced increases in cyclic nucleotides, slightly blocked TRH-effects, and had no effect on Apo-effects. These in vivo results were confirmed in an in vitro system using brain slices. The addition of DN-1417 (10(-4) M) or TRH (10(-3) M) significantly enhanced the spontaneous [3H]-dopamine and [3H]-norepinephrine release from the superfused slices of the rat nucleus accumbens and cerebral cortex in vitro. The addition of DN-1417 (10(-4) M) or TRH (10(-4) M) had no effect on the activities of adenylate cyclase and guanylate cyclase, although only a high concentration (10(-3) M) of DN-1417 inhibited the cyclic AMP- and cyclic GMP-hydrolytic activities in various brain region homogenates. These results suggest that DN-1417 does not produce an increase in the levels of cyclic nucleotides by direct receptor-enzyme activation, but that DN-1417 like MAP causes the increase through endogenous catecholaminergic, particularly dopaminergic activation.     

Behavioral evaluation of psycho-pharmacological and psychotoxic actions of methylxanthines by ambulatory activity and discrete avoidance in mice.

The behavioral effects of methylxanthines, caffeine, theophylline and theobromine, were compared by means of ambulatory activity and discrete lever-press avoidance response in mice. The single oral administration of 10-100 mg/kg of caffeine, 30-300 mg/kg of theophylline, and 10 mg/kg of theobromine significantly increased the mouse's ambulatory activity. However, 1000 mg/kg of theobromine decreased the activity. The ambulation-increasing effect of methamphetamine (2 mg/kg s.c.) was enhanced by coadministration with caffeine (3-100 mg/kg), theophylline (10-300 mg/kg), and theobromine (10-100 mg/kg). On the other hand, comparatively higher doses of caffeine (up to 30 mg/kg) slightly but significantly decreased the avoidance rate without eliciting any significant change in the response rate. Theobromine significantly decreased the response rate at higher than 300 mg/kg, and the avoidance rate at higher than 100 mg/kg. Furthermore, 1000 mg/kg of theobromine was much toxic for mice, i.e., half mice died within a few hr after the end of the 1-hr avoidance session. Theophylline did not produce any significant change in the avoidance response at the dose range of 3-300 mg/kg. These results may indicate the relative order of the centrally stimulant and/or behavioral toxic actions of methylxanthines in human.     

Acute and chronic morphine treatment and the hydroxylation of [1-14C]-L-Tyrosine in the mouse brain

Tyrosine hydroxylase activity in slices of caudate nucleus was increased by morphine (100 mg/kg i.p.) administered to naive mice. During chronic treatment with morphine tolerance developed to this effect and 36 h after the final chronic morphine injection there was a decrease in enzyme activity in this area. There was no change in tyrosine hydroxylase activity in slices of diencephalon, brainstem or parietal cortex from either naive or morphine tolerant mice. There- fore, changes in tyrosine hydroxylase activity, measured in vitro, could account for the changes in dopamine synthesis, but not noradrenaline synthesis, produced by morphine in vivo.     

Effects of dietary tyrosine on L-dopa- and amphetamine-induced changes in locomotor activity and neurochemistry in mice

Recent findings suggest that intraperitoneal injections of L-tyrosine at high doses (100 mg/kg) alters amphetamine-induced changes in behavior by restoring amphetamine-induced decreases in whole brain norepinephrine (NE). The present study examined the motor effects of L-dihydroxyphenylalanine (L-dopa) and d-amphetamine sulfate in mice after treatment with a basal casein diet supplemented with L-tyrosine. The basal diet supplemented with 1-4% L-tyrosine, or 1-4% L-phenylalanine, produced no changes in motor activity in otherwise untreated mice. Whereas L-dopa (25-100 mg/kg) following inhibition of extracerebral decarboxylase by Ro 4-4602 (25 mg/kg) slightly decreased activity in diet control (casein) animals, this drug treatment enhanced motor activity in a dose-related fashion when L-tyrosine was added to the diet. Increases in motor activity following low doses of amphetamine (0.75-1.5 mg/kg) in casein control mice were antagonized by dietary L-tyrosine, but a higher dose of d-amphetamine (3 mg/kg) interacted with the addition of L-tyrosine producing an increase in motor activity. Neurochemical changes observed in brain concentrations of tyrosine, dopamine (DA), norepinephrine (NE), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), tryptophan, serotonin (5-HT) and 5-hydroxy-indoleacetic acid (5-HIAA) following drug and diet treatments suggest that 5-HT systems, in addition to catecholamine systems, may be involved in mediating these effects.     

Behavioral effects of caffeine, (-)N-((R)-1-methyl-2-phenylethyl)-adenosine (PIA), and their combination in the mouse

The effects of caffeine (1–100 mg/kg, IP), (-)N-((R)-1-methyl-2-phenylethyl)-adenosine (PIA) (0.01–1 mg/kg, IP), and of the two drugs in combination were studied in mice responding under a mult FR30 FI600 s schedule of food presentation. The lowest dose of caffeine, 1 mg/kg, had no effect on responding under either component of the mult schedule. Intermediate doses of caffeine (3 and 10 mg/kg) slightly increased responding under the FI component, while higher doses decreased responding. Caffeine only decreased responding, at doses above 30 mg/kg, under the FR component. PIA decreased responding under both components of the mult schedule in a dose-dependent, and similar, manner. In most cases, the rate-increasing effect of caffeine on FI responding was diminished when combined with a rate-decreasing dose of PIA. However, when 0.01 mg/kg PIA, a dose that had no effect alone, was combined with 3 mg/kg caffeine, the increase in rate exceeded that of caffeine alone. Rate-deceasing effects of PIA were antagonized by caffeine; with larger doses of PIA, larger doses of caffeine were required for antagonism. Thus, while the rate-increasing effects of caffeine can be either enhanced or diminished, when combined with different doses of PIA, the rate-decreasing effects of PIA are clearly antagonized by caffeine in a dose-dependent manner.     

The effect of LHRH on rat conditioned avoidance behavior: interaction with brain catecholamines

LHRH (100 micrograms/kg. SC) impairs the acquisition of two-way avoidance conditioning. This is partially potentiated by pretreatment with alpha-methyltyrosine (alpha-MT; 250 mg/kg IP) or fusaric acid (10 mg/kg IP). L-DOPA (100 mg/kg IP) administered 5 h after alpha-MT partially reversed its effects. The possible roles of brain catecholamines on the behavioral effects of LHRH are analysed. Other tentative mechanisms of action are also discussed.     

Tissue distribution of 2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione (NTBC) and its effect on enzymes involved in tyrosine catabolism in the mouse

Administration of a single oral dose of 2-(2-nitro-4-trifluoromethyl-benzoyl)-cyclohexane-1,3-dione (NTBC) to mice increases the concentration of tyrosine in the plasma and aqueous humour. The tyrosinaemia is both time and dose-dependent with a single dose of 30 micromol NTBC/kg (10 mg/kg) producing maximal concentrations of tyrosine in plasma of about 1200 nmol/ml and in aqueous humour of about 2200 nmol/ml at 16 h after dosing. Analysis of the key hepatic enzymes involved in tyrosine catabolism, following a single dose of 30 micromol NTBC/kg, showed that 4-hydroxyphenylpyruvate dioxygenase (HPPD) was markedly inhibited soon after dosing and that the activity recovered very slowly. In response to the tyrosinaemia, the activity of hepatic tyrosine aminotransferase (TAT) was induced about two-fold, while the activity of hepatic homogentisic acid oxidase (HGO) was reduced at 4 and 5 days after dosing. Daily oral administration of NTBC at doses up to 480 micromol NTBC/kg (160mg/kg/day) to mice produced a maximal tyrosinaemia of about 600-700nmol/ml plasma, showing some adaptation relative to a single dose. Unlike the rat, no treatment-related corneal lesions of the eye were seen at any dose levels up to 6 weeks. Administration of a single oral dose of [14C]-NTBC at 30 micromol/kg led to selective retention of radiolabel in the liver and to a lesser extent the kidneys. Our studies show that NTBC is a potent inhibitor of mouse liver HPPD, which following repeat exposure produces a marked and persistent tyrosinaemia, which does not result in ocular toxicity.     

1-(2,6-二甲基苯氧基)-2-(3,4-二甲氧基苯乙胺基)丙烷盐酸盐对实验性高血压大鼠的降压作用

DDPH 3～10 mg/kg iv降低DOCA—盐型及自发性高血压(SH)大鼠的MAP及HR;50,100mg/kg ig降低清醒正常血压及SH大鼠MAP及HR·心率减慢较降压作用持续时间短。DDPH(10,100μmol/L)对犬乳头状肌收缩力及静息30 s后第一次收缩(PRC_(30))有抑制作用。小鼠ig DDPH的LD_(50)为640 mg/kg,95％可信限为567～713mg/kg。麻醉大鼠静脉恒速灌注DDPH的致死量为47±SD 4 mg/kg。表明DDPH对实验性高血压大鼠有降压作用,并对心肌收缩力及肌浆网Ca~(2+)的释放有轻度抑制作用。     

Single dose toxicity study on catena-(S)-[mu-[N alpha-(3-aminopropionyl) histidinato(2-)-N1,N2,O:N tau]-zinc] in mice and rats.

The toxicity of Z-103 (catena-(S)-[mu-[N alpha-(3-aminopropionyl) histidinato(2-)-N1,N2,O:N tau]-zinc], CAS 107667-60-7) was evaluated in mice and rats after single administration. LD50 values in mice were 1269 mg/kg for males and 1331 mg/kg for females by the oral route, 220 mg/kg for males and 165 mg/kg for females by the intraperitoneal route, and 758 mg/kg for males and 874 mg/kg for females by the subcutaneous route. LD50 values in rats were 8441 mg/kg for males and 7375 mg/kg for females by the oral route, 405 mg/kg for males and 422 mg/kg for females by the intraperitoneal route and more than 5000 mg/kg for both sexes by the subcutaneous route. No sex differences were observed. A decrease in locomotor activity, ventral posture, crouching, hypothermia and respiratory depression were observed in both mice and rats as the main clinical signs. In addition to these changes, induration, swelling and crust formation were observed at the subcutaneous injection site.     

Novel cerebroprotective agents with central nervous system stimulating activity. 2. Synthesis and pharmacology of the 1-(acylamino)-7-hydroxyindan derivatives.

In a continuous search for a novel cerebroprotective drug with a central nervous system (CNS) stimulating activity, a series of 1-(acylamino)-7-hydroxyindan derivatives has been synthesized and tested for its dual activities. The cerebroprotective activities of the compounds in this series were evaluated in terms of their effect on the survival of mice in hypoxic conditions (210 mmHg), and their CNS stimulating activities were examined by evaluating their promotional effects on the recovery from coma induced by cerebral concussion in mice. Several compounds prolonged the survival of mice in the hypoxic conditions at a dose of 30 mg/kg po. Four compounds in this series showed the CNS-stimulating effect at the same dose. Among them, 7-hydroxy-1-[4-(3-methoxyphenyl)-1-piperazinyl]acetyl]amino]-2,2,4, 6-tetramethylindan (18, OPC-14117), which was active in the two tests with no side effect up to 500 mg/kg po daily for 2 weeks of administration to rats, was selected for preclinical investigations.     

Effect of 4-(o-benzylphenoxy)-N-methylbutylamine hydrochloride (bifemelane hydrochloride, MCI-2016) on cerebral glucose metabolism

To predict the influence of MCI-2016 on cerebral energy metabolism, the activity of MCI-2016 on uptake of 2-deoxy-D-[14C]glucose ([14C]-DG) into the brain under normal or hypoxic conditions, formation of 14CO2 from 14C-glucose in the brain, and local cerebral glucose utilization (LCGU) were examined. Cerebral uptake of [14C]-DG in mice were significantly enhanced by 6 day repeated administration of MCI-2016 (25 mg/kg, i.p.) and Ca-hopantenate (100 mg/kg, i.p.). The two drugs showed a slight enhancing effect on [14C]-DG uptake after single administration. As an index of cerebral glucose metabolism, 14CO2 formation from 14C-glucose was also stimulated by 6 day repeated administration of MCI-2016 (100 mg/kg, p.o., mice and rats) and Ca-hopantenate (250 mg/kg, i.p., rats). MCI-2016 moderately attenuated the decreased [14C]-DG uptake under the hypoxic condition in rats after 6 day repeated administration (100 mg/kg, p.o.). In addition, local cerebral glucose utilization (LCGU) in rats was also significantly potentiated by MCI-2016 (100 mg/kg, p.o., 6 days) in the areas of the visual cortex, thalamus ventral nucleus and uvula. From these results, MCI-2016 may be suggested to have a moderate activating effect on cerebral energy metabolism.     

General pharmacology of 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate. 1st communication: effects on the central nervous system

Effects of 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate (KB-2413) on the central nervous system were compared with those of ketotifen and chlorpheniramine. Among the various activities related to the central nervous system, KB-2413 showed inhibitory effects on locomotor activity, acetic acid-induced writhing in mice and reserpine-induced hypothermia in rats at a high dose such as 100 mg/kg p.o. However, in mice, it (10-100 mg/kg p.o.) exerted no significant influence on muscle tone, various experimental convulsions, oxotremorine-induced tremor, physostigmine-induced mortality or hexobarbital-induced sleep, and in rats, it had no effect on rectal temperature or conditioned avoidance. It also did not affect spontaneous electroencephalogram (EEG), EEG arousal responses or photic driving response in rabbits at 5 mg/kg i.v. On the other hand, ketotifen and chlorpheniramine affected more widely and strongly the central nervous system than KB-2413. In conclusion, KB-2413 showed a less potent effect on the central nervous system than ketotifen and chlorpheniramine, and no results suggested serious side effects of KB-2413.     

The anxiolytic-like profile of the nociceptin receptor agonist, endo-8-[bis(2-chlorophenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octane-3-carboxamide (SCH 655842): comparison of efficacy and side effects across rodent species

The endogenous opioid-like peptide, nociceptin, produces anxiolytic-like effects that are mediated via the nociceptin (NOP) receptor. Similarly, synthetic, non-peptide NOP agonists produce robust anxiolytic-like effects although these effects are limited by marked side effects. In the present studies, the effects of a novel NOP receptor agonist, SCH 655842, were examined in rodent models sensitive to anxiolytic drugs and tests measuring potential adverse affects. Oral administration of SCH 655842 produced robust, anxiolytic-like effects in three species, i.e., rat, guinea pig, and mouse. Specifically, SCH 655842 was effective in rat conditioned lick suppression (3-10 mg/kg) and fear-potentiated startle (3-10 mg/kg) tests, a guinea pig pup vocalization test (1-3 mg/kg), as well as in mouse Geller-Seifter (30 mg/kg) and marble burying (30 mg/kg) tests. The anxiolytic-like effect of SCH 655842 in the conditioned lick suppression test was attenuated by the NOP antagonist, J-113397. In mice, SCH 655842 reduced locomotor activity and body temperature at doses similar to the anxiolytic-like dose and these effects were absent in NOP receptor knockout mice. In rats, SCH 655842 did not produce adverse behavioral effects up to doses of 70-100 mg/kg. Pharmacokinetic studies in the rat confirmed dose-related increases in plasma and brain levels of SCH 655842 across a wide oral dose range. Taken together, SCH 655842 may represent a NOP receptor agonist with improved tolerability compared to other members of this class although further studies are necessary to establish whether this extends to higher species.