Sedative-hypnotic Activity Research Articles

English

English

ChemInform Abstract: Synthesis and Sedative-Hypnotic Effects of N3-Allyl- and N1-Allyl-5,6-Substituted 2-Thiouracil Derivatives in Mice.

Twenty four thiouracil derivatives, including N3-allyl- (19) and N1-allyl-2-thiouracil (20) were synthesized and their pharmacological effects [sedative-hypnotic activity (loss of righting reflex and spontaneous activity), convulsant activity, effect on pentobarbital (PB)-induced sleep and mortality] were evaluated in mice at doses of 320 mg/kg, i.p. and 2 μmol/mouse by intracerebroventricular (i.c.v.) injections, respectively. N3-Allyl-6-propyl-2-thiouracil (3), N3-allyl-5, 6-dimethyl-2-thiouracil (10), N3-allyl-1, 2, 3, 4, 5, 6, 7, 8, 9-nonahydro-4-oxo-2-thiocyclohepta[d]pyrimidine (16) and N3-allyl-5-methyl-2-thiouracil (18) exhibited sedative-hypnotic activity, whereas N3-allyl-6-ethyl-5-methyl-2-thiouracil (11), N1-allyl-5-methyl-2-thiouracil (21), N1-allyl-1, 2, 3, 4, 5, 6, 7, 8, 9-nonahydro-4-oxo-2-thiocyclohepta[d]pyrimidine (23) and N1-allyl-5, 6-dimethyl-2-thiouracil (24) conversely displayed clonic- and/or tonic-convulsant seizures. N3-Allyl-6-propyl-2-thiouracil (3) and N3-allyl-5-methyl-2-thiouracil (18) decreased spontaneous activity. Other compounds examined were inactive, or only slightly active in the sedative-hypnotic assay even at high doses. Fifteen compounds (1-4, 7, 10, 11, 14-16, 18-21, and 23) significantly prolonged the PB-induced sleeping time. Interestingly, only N1-allyl-5, 6-dimethyl-2-thiouracil (24) shortened the PB-induced sleeping time. These results showed that these thiouracils possessed many different effects such as sedative-hypnotic, anticonvulsant and/or convulsant, and that N3-allyl-5-methly-2-thiouracil (18) and N1-allyl-5, 6-dimethyl-2-thiouracil (24) had the most potent hypnotic activity and antagonistic effect against PB, respectively.

Anxiolytic and sedative-hypnotic activities of polygalasaponins from Polygala tenuifolia in mice

In the present study, the anxiolytic and sedative-hypnotic activities of polygalasaponins extracted from Polygala tenuifolia Willdenow (Polygalaceae) were determined in mice using hole-board, elevated plus maze, open field, and sodium pentobarbital-induced hypnosis tests. Moreover, the acute toxicity of polygalasaponins was also estimated in mice. Sixty minutes after p.o. administration of polygalasaponins (40, 80, 160 mg/kg) in mice, the central crossing counts and percentage of central/total ambulation significantly increased and the number of rearings and defecations was evidently inhibited in the open field test. Polygalasaponins also increased the head-dips of mice in the hole-board test and the time spent by mice in the open arms of the X-maze, prolonged sleep duration and shortened sleep latency in the test of synergetic effect on sodium pentobarbital (45 and 25 mg/kg, respectively). Acute toxic study showed the oral median lethal dose (LD50) of polygalasaponins was 3.95 g/kg and 0% lethal dose 2.6 g/kg. These results suggest that polygalasaponin possesses evident anxiolytic and sedative-hypnotic activities and has a relatively safe dose range, which supports the use of Polygala tenuifolia root as an anxiolytic and sedative-hypnotic drug in folk medicine.

Synthesis and calming activity of 6H-2-Amino-4-Aryl-6-(4-β-D-Allopyranosyloxyphenyl)-1,3-Thiazine

E-(4-β-D-Allopyranosyloxyphenyl)-1-(4-substituted phenyl)propenone derivatives (1a–g) have been synthesized by the Claisen-Schmidt condensation of helicid with 4-substituted acetophenone using 10% NaOH aqueous solution as a catalyst. 6H-2-Amino-4-aryl-6-(4-β-D-allopyranosyloxyphenyl)-1,3-thiazine (2a–g) were synthesized by the 1,4-Michael reaction of 1a–g with thiourea. The structures of all the new products were established by 1H NMR, IR, and MS spectroscopy. Compound 2b (200 mg·kg–1) showed better sedative-hypnotic activity, so further modification of helicid should be worthwhile.

Pharmacological studies on the sedative-hypnotic effect of Semen Ziziphi spinosae (Suanzaoren) and Radix et Rhizoma Salviae miltiorrhizae (Danshen) extracts and the synergistic effect of their combinations

Semen Ziziphi spinosae (Suanzaoren in China) and Radix et Rhizoma Salviae miltiorrhizae (Danshen in China) are conventional herbal drugs in traditional Chinese medicine and have been used widely for the treatment of insomnia. In the present study, the sedative-hypnotic activity of the active fractions extracted from Suanzaoren and Danshen were studied using the method of pentobarbital-induced sleep in the mouse model. Qualitative analysis of the standardized extracts was carried out by HPLC-DAD. The results showed that the water extract of Suanzaoren (SWE) (400 and 800 mg/kg body wt.) and the ether extract of Danshen (DTT) (300 and 600 mg/kg body wt.) can shorten sleep latency significantly, increase sleeping time and prolong movement convalescence time induced by sodium pentobarbital (55 mg/kg body wt.) administration in mice. Furthermore, the combination of SWE and DTT showed significant synergistic effect (p<0.05) in decreasing sleep latency and increasing sleeping time, but not in prolonging the movement convalescence time, which might be helpful for energy recovery in the treatment of insomnia. The results suggest that SWE, DTT, and the combination of SWE and DTT possess significant sedative-hypnotic activity, which supports the popular use of Suanzaoren and Danshen for treatment of insomnia and provide the basis for new drug discovery. Furthermore, the results demonstrate that the combination of SWE and DTT may be preferable for the treatment of insomnia.

Synthesis, anticonvulsant and CNS depressant activity of some new bioactive 1-(4-substituted-phenyl)-3-(4-oxo-2-phenyl/ethyl-4 H-quinazolin-3-yl)-urea

Several new 1-(4-substituted-phenyl)-3-(4-oxo-2-phenyl/ethyl-4 H-quinazolin-3-yl)-urea were synthesized and screened for anticonvulsant, CNS depressant and sedative-hypnotic activity in the mice. After i.p. injection to mice at doses of 30, 100, and 300 mg/kg body weight synthesized compounds were examined in the maximal electroshock induced seizures (MES) and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in mice. Spectroscopic data and elemental analysis were consistent with the newly synthesized compounds. The neurotoxicity was assessed using the rotorod method. Compounds E1, E6, E9, E12, P3, P4 and P6 were found to be active in the MES screen whereas E1, P4, P6 and P11 were found to be active in the scPTZ screen. All except E6, E11 and P6 showed more than 50% decrease in locomotor activity at 1 h of compound administration via actophotometer screen. CNS depressant activity screened with the help of the forced swim method resulted into some potent compounds. All the compounds were found to exhibit potent CNS depressants activity as indicated by increased immobility time. It can be concluded that newly synthesized compounds possessed promising CNS activities.

Anticonvulsant and sedative-hypnotic activity of some novel 3-[5-(4-substituted) phenyl-1,3,4-oxadiazole-2yl]-2-styrylquinazoline-4(3H)-ones

A few novel 3-[5-(4-substituted) phenyl-1,3,4-oxadiazole-2-yl]-2-styryl quinazoline-4(3H)-ones were synthesized and evaluated for anticonvulsant, neurotoxicity, sedative-hypnotic, and phenobarbitone-induced hypnosis potentiation test. After i.p. injection to mice at doses of 30, 100, and 300 mg/kg body weight derivatives were examined in the maximal electroshock-induced seizures (MES) and subcutaneous pentylenetetrazole (scPTZ)-induced seizure models in mice. Spectroscopic data were consistence with the newly synthesized compounds. The neurotoxicity was assessed using the Rotorod method. Out of 15 compounds only 7e and 7o showed anticonvulsant activity at various doses in one or more test models. All except 7d, 7m, and 7n exhibited significant sedative-hypnotic activity via actophotometer screen. Central nervous system (CNS)-depressant activity screened with the help of the forced swim method resulted into some potent compounds. No percentage increase in the sleeping time was observed in any of the synthesized compounds evaluated by the phenobarbitone-induced hypnosis potentiation test. On the basis of experimental data, it can be concluded that synthesized compounds possessed relatively better sedative-hypnotic and CNS-depressant activities.

Synthesis and anticonvulsant activity of some substituted 1,2,4-thiadiazoles

A series of new substituted 1,2,4-thiadiazoles were synthesized by appropriate route and screened for anticonvulsant, neurotoxic and sedative-hypnotic activity. The structures of the synthesized compounds were confirmed by IR spectroscopy, 13C NMR and elemental (nitrogen and sulphur) analysis. After i.p. injection of the compounds to mice or rate at doses of 30, 100, and 300 mg/kg, body weights were examined in the maximal electroshock-induced seizures (MES) and subcutaneous pentylenetetrazole (scPTZ)-induced seizure models after 0.5 and 4 h. Rotorod method and phenobarbitone-induced hypnosis potentiation study were employed to examine neurotoxicity and sedative-hypnotic activity, respectively. All the compounds except 4g showed protection against MES screen after 0.5 h. Compounds 3a– c, 4a– c were active at 100 mg/kg dose i.p., whereas remaining compounds showed activity at 300 mg/kg. All 14 compounds except 3 g showed neurotoxicity at 100 and 300 mg/kg after 0.5 h. Compounds 3b and 4b showed NT after 4 h. Two compounds 3b and 4g showed significant ( p < 0.05) percentage increase in sleeping time i.e. 67% and 59%, respectively. It may be concluded that the synthesized compounds were potent against MES-induced seizures than ScPTZ induced and showed low potency as sedative-hypnotic agent which is advantageous.

ChemInform Abstract: Novel Water‐Soluble Sedative‐Hypnotic Agents: Isoindolin‐1‐one Derivatives.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Anticonvulsant and Sedative-Hypnotic Activities of N-Acetyl / Methyl Isatin Derivatives

A series of N-methyl/acetyl 5-(un)-substituted isatin-3-semicarbazones were screened for anticonvulsant and sedative-hypnotic activities. The results revealed that protection was obtained in all the screens i.e., Maximal electroshock, (MES) subcutaneous pentylene tetrazole (scPTZ) and subcutaneous strychnine (scSTY) screens. Three compounds (5a, 5e and 5i) possessed anti-MES activity and all the compounds were less neurotoxic than phenytoin, carbamazepine and phenobarbital. All the compounds were completely non-toxic at 4h when compared to phenytoin, carbamazepine and phenobarbital, which were toxic at 100 and 300 mg/kg respectively. Compounds 5a, 5b, 5e, 5g and 5i emerged as the active compounds in oral MES screen. Selected compounds were evaluated for quantification studies in MES, scPTZ and neurotoxicity screens after i. p (5b, 5i) and oral administration (5a, 5g) in rats. Among all the compounds 5a, 5b and 5g emerged as broad-spectrum compounds as indicated by their protection in MES, scSTY and scPTZ screens. All the compounds except compound 5b showed significant sedative-hypnotic activity.

Expeditious Synthesis of 1,3,4-Trisubstituted Pyrazoles from Baylis-Hillman Adducts

The pyrazole nucleus is present in a wide variety of biologically interesting compounds, which exhibit antihyperglycemic, analgesic, anti-inflammatory, antipyretic, antibacterial, hypoglycemic, sedative-hypnotic activity. Thus, continuous efforts have been devoted to the development of more general and versatile synthetic methodologies to this class of compounds. Recently we have reported on the regio-selective synthesis of 1,3,4,5-tetrasubstituted pyrazole derivatives from the reaction of Baylis-Hillman adducts of alkyl vinyl ketone and hydrazine derivatives (Scheme 1). During the continuous studies on the chemical transformations of Baylis-Hillman adducts including the synthesis of pyrazoles we presumed that we could synthesize 1,3,4-trisubstituted pyrazoles from the reaction of hydrazine derivatives and acyloxiranes, which could be synthesized easily from Baylis-Hillman adducts (Scheme 2). According to the reported method, the required acyloxiranes 2a-e were synthesized in moderate yields from the corresponding Baylis-Hillman adducts 1 by NaOCl in the presence of silica gel in acetonitrile. With these acyloxiranes 2a-e in our hands, we examined the synthesis of corresponding pyrazoles under a variety of conditions, and we found that the reaction of 2a-e and various hydrazine hydrochlorides in 1,2-dichloroethane at refluxing temperature afforded the best results. As shown in Table 1, the reaction of 2a with phenylhydrazine hydrochloride, tertbutylhydrazine hydrochloride, 2,4-difluorophenylhydrazine hydrochloride afforded 3a-c in moderate yields (39-75%). In the reaction of 2,4-dinitrophenylhydrazine (entry 4), we used p-toluenesulfonic acid as the acid catalyst. Other acyloxiranes 2b-e showed similar results in the reactions of phenylhydrazine hydrochloride (36-71%, entries 5-8). Although we isolated the products in moderate yields in most cases, however, the yields of 3b and 3f were relatively low due to the formation of many intractable side products. In summary, we disclosed an expeditious synthesis of 1,3,4-trisubstituted pyrazoles from the reaction of hydrazine derivatives and the acyloxiranes, which were prepared from Baylis-Hillman adducts.

Synthesis and CNS depressant activity of some novel 3-[5-substituted 1,3,4-thiadiazole-2-yl]-2-styryl quinazoline-4(3 H)-ones

A series of novel 3-[5-substituted phenyl-1,3,4-thiadiazole-2-yl]-2-styryl quinazoline-4(3 H)-ones were synthesized and evaluated for anticonvulsant, sedative-hypnotic and CNS depressant activities. After i.p. injection to mice at doses of 30, 100, and 300 mg/kg body weight 2-styrylquinazolin-4(3 H)-one derivatives were examined in the maximal electroshock induced seizures (MES) and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in mice. The neurotoxicity was assessed using the rotorod method. Out of eighteen compounds only 4a, 4d, 4e, 4j and 4k showed anticonvulsant activity in one or more test models. All except 4e and 4f exhibited significant sedative-hypnotic activity via actophotometer screen. CNS depressant activity screened with the help of the forced swim pool method resulted into some potent compounds. From the experimental observation it can be concluded that synthesized compounds exhibited relatively better sedative-hypnotic and CNS depressant activities.

Novel Water-Soluble Sedative-Hypnotic Agents: Isoindolin-1-one Derivatives

We developed new intravenous sedative-hypnotic compounds with the isoindolin-1-one skeleton focusing on the water-soluble property and in vivo safety. We synthesized approximately 170 derivatives and evaluated their hypnotic effects by intravenous administration of the compounds to mice. A series of the 2-phenyl-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]isoindolin-1-one analogs, 3(-), 5(-), 27(-), and 47(-) [JM-1232(-)], showed potent sedative-hypnotic activity with good water solubility and a wide safety margin. The hypnotic doses (HD50s) of these 4 compounds when administered to mice were 2.35, 1.90, 2.17, and 3.12 mg/kg, respectively, and the lethal doses (LD50s) were 88.67, 64.69, >120, and >120 mg/kg, respectively. The therapeutic indexes (LD50/HD50) were 37.73, 34.05, >55.30, and >38.46, respectively. Among these compound, 47(-) [JM-1232(-)] is being considered as the most potential candidate for clinical trials in humans.

Synthesis, crystal structures, and anti-convulsant activities of ternary [Zn II(3,5-diisopropylsalicylate) 2], [Zn II(salicylate) 2] and [Zn II(aspirinate) 2] complexes

Following observations that bis(3,5-diisopropylsalicylato)diaquazinc II, [Zn II(3,5-DIPS) 2(H 2O) 2], had anti-convulsant activity, bis(acetylsalicylate)diaquazinc II, [Zn II(aspirinate) 2(H 2O) 2], and the Zn II ternary 1,10-phenanthroline (phen), 2,9-dimethyl-1,10-phenanthroline (neocuproine, NC) or dimethyl sulfoxide (DMSO) complexes of Zn II3,5-diisopropylsalicylate, salicylate, and acetylsalicylate were synthesized and spectroscopically characterized. Anti-convulsant and Rotorod toxicity activities of these complexes were determined to examine their anti-convulsant and undesirable central nervous stimulant or depressant activities of these Zn II non-steroidal anti-inflammatory agent complexes. Bis(3,5-diisopropylsalicylato)-1,10-phenanthorlinezinc II, [Zn II(3,5-DIPS) 2(phen)], ( 1) has one bidentate phen ligand and two mono-deprotonated 3,5-DIPS ligands. One of the carboxylates bonds in an asymmetric chelating mode. The Zn II atom exhibits a distorted bicapped rectangular pyramidal environment N 2O 2OO (4 + 1 + 1∗). In the neocuproine complex, bis(3,5-diisopropylsalicylato)-2,9-dimethyl-1,10-phenanthorlinezinc II, [Zn II(3,5-DIPS) 2(NC)] ( 2), the Zn II atom has a much more distorted bicapped rectangular pyramidal environment, N 2O 2O 2 (4 + 2∗), compared to 1. The two carboxylate ligands exhibit the same asymmetric coordinating mode with longer metalloelement–oxygen bond distances compared to 1. The space group of [Zn II(aspirinate) 2(H 2O) 2] ( 3), which has been reported as Cc is corrected to C2/c. The zinc atom exhibits a (4 + 2∗) bicapped square pyramidal environment. While the two ternary phenanthroline-containing complexes, 1 and 2, evidenced weak protection against maximal electroshock (MES)- and subcutaneous Metrazol (scMET) induced seizures, [Zn II(3,5-DIPS) 2(DMSO) 2], [Zn II(aspirinate) 2(H 2O) 2], and bis(salicylato)-1,10-phenanthorlinezinc II, [Zn II(salicylate) 2(phen)], were found to be particularly useful in protecting against MES and scMET seizures and [Zn II(aspirinate) 2(H 2O) 2] and [Zn II(salicylate) 2(phen)] were found to have activity in protecting against Psychomotor seizures, without causing Rotorod toxicity. Activities of these and other Zn II complexes of non-steroidal anti-inflammatory agents are consistent with the well-known anti-inflammatory responses of Zn II-dependent enzymes. There was also some evidence of Rotorod toxicity consistent with a mechanism of action involving sedative-hypnotic activity of recognized anti-epileptic drugs.

4-Sulphamoylphenyl semicarbazones with anticonvulsant activity

A series of 4-sulphamoylphenyl semicarbazone derivatives were prepared starting from sulphanilamide and screened for anticonvulsant activity. The results indicated that greater protection was obtained in the maximal electroshock screen (MES) and subcutaneous strychnine (scSTY) than the subcutaneous pentylenetetrazole (scPTZ) tests. All the compounds showed low neurotoxicity when compared to the clinically used drugs. Compounds with substituted acetophenone ( 8-11) showed good activity in the rat oral MES screen. Seven compounds ( 6, 8-10, 12, 14 and 15) exhibited anticonvulsant activity greater than sodium valproate. Among the new derivatives evaluated, compound 10 emerged as the most active compound as indicated by its protection in the MES and scSTY screens and with low neurotoxicity. Seven compounds possessed sedative-hypnotic activity.

Anticonvulsant and Sedative‐Hypnotic Activities of N‐Substituted Isatin Semicarbazones

AbstractFor Abstract see ChemInform Abstract in Full Text.

Anticonvulsant and sedative-hypnotic activities of N-substituted isatin semicarbazones.

A series of N-methyl/acetyl, 5-(un)-substituted isatin-3-semicarbazones were screened for anticonvulsant and sedative-hypnotic activities. The results revealed that protection was obtained in all the screens i.e., MES, scPTZ, and scSTY. Compounds 2, 4, 6, 10 but not 1 and 3 showed low neurotoxicity when compared to clinically used drugs. Compounds 5, 7, 8 and 9 were completely non-toxic. Compound 6 showed good activity in the rat oral MES screen. Among all the compounds, 3 and 6 emerged as the most active compounds as indicated by the protection they exhibit in MES, scSTY, and scPTZ screens. All the compounds showed significant sedativehypnotic activity.

Synthesis and anticonvulsant activity of 4-bromophenyl substituted aryl semicarbazones

A number of 4-bromophenyl semicarbazones were synthesised and evaluated for anticonvulsant and sedative–hypnotic activities. After intraperitoneal injection to mice, the semicarbazone derivatives were examined in the maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (scPTZ), subcutaneous strychnine (scSTY) and neurotoxicity (NT) screens. All the compounds showed anticonvulsant activity in one or more test models. Compound 12 showed greatest activity, being active in all the screens with very low neurotoxicity and no sedative–hypnotic activity. All the compounds except 7 had lower neurotoxicity compared to phenytoin. Three compounds ( 6, 11 and 14) showed greater protection than sodium valproate. The essential structural features responsible for interaction with receptor site are established within a suggested pharmacophore.

Synthesis and sedative-hypnotic effects of N3-allyl- and N1-allyl-5,6-substituted 2-thiouracil derivatives in mice.

Twenty four thiouracil derivatives, including N3-allyl- (19) and N1-allyl-2-thiouracil (20) were synthesized and their pharmacological effects [sedative-hypnotic activity (loss of righting reflex and spontaneous activity), convulsant activity, effect on pentobarbital (PB)-induced sleep and mortality] were evaluated in mice at doses of 320 mg/kg, i.p. and 2 mumol/mouse by intracerebroventricular (i.c.v.) injections, respectively. N3-Allyl-6-propyl-2-thiouracil (3), N3-allyl-5,6-dimethyl-2-thiouracil (10), N3-allyl-1,2,3,4,5,6,7,8,9-nonahydro-4-oxo-2-thiocyclohepta [d]pyrimidine (16) and N3-allyl-5-methyl-2-thiouracil (18) exhibited sedative-hypnotic activity, whereas N3-allyl-6-ethyl-5-methyl-2-thiouracil (11), N1-allyl-5-methyl-2-thiouracil (21), N1-allyl-1,2,3,4,5,6,7,8,9-nonahydro-4-oxo-2-thiocyclohepta[ d]pyrimidine (23) and N1-allyl-5,6-dimethyl-2-thiouracil (24) conversely displayed clonic- and/or tonic-convulsant seizures. N3-Allyl-6-propyl-2-thiouracil (3) and N3-allyl-5-methyl-2-thiouracil (18) decreased spontaneous activity. Other compounds examined were inactive, or only slightly active in the sedative-hypnotic assay even at high doses. Fifteen compounds (1-4, 7, 10, 11, 14-16, 18-21, and 23) significantly prolonged the PB-induced sleeping time. Interestingly, only N1-allyl-5,6-dimethyl-2-thiouracil (24) shortened the PB-induced sleeping time. These results showed that these thiouracils possessed many different effects such as sedative-hypnotic, anticonvulsant and/or convulsant, and that N3-allyl-5-methyl-2-thiouracil (18) and N1-allyl-5,6-dimethyl-2-thiouracil (24) had the most potent hypnotic activity and antagonistic effect against PB, respectively.

Cyclic ureas. 2. Racemates and enantiomers of imidazolidin-2-ones: synthesis, configuration and sedative-hypnotic action

The racemates and the enantiomers of the imidazolidin-2-ones 2a and 2b, which can be considered as cyclic ureas, are obtained from the racemates and the enantiomers of the hydantoins 1a and 1b by reduction with LiAlH4/AlCl3. The enantiomers that are dextrorotating in ethanol possess S-configuration. In a study with Wistar-rats, 2a and 2b show sedative-hypnotic activity. The enantiomers exhibit marked enantioselective differences in their potency.