Potential anticonvulsants. 1. 5-Benzylhydantoins

Mehta, Nariman B.; Diuguid, C. A. Risinger; Soroko, Francis E.

doi:10.1021/jm00136a018

Cited by 70 publications

(37 citation statements)

References 3 publications

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“…The ED50 is approx. 8 mg/kg in mice (1,2). In our hands, the ED50 is 11 mg/kg (P.T.-H. Wong and S.-F. Tan, un published).…”

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confidence: 57%

“…In our hands, the ED50 is 11 mg/kg (P.T.-H. Wong and S.-F. Tan, un published). Vida et al (3) reported that two methyl derivatives of phenytoin, 3-methyl phenytoin (3-MP) and 1,3-dimethylpheny toin (1,, are effective against MES in mice with ED50 values of about 5 and 50 mg/kg, respectively. Peak activities for 3-MP, 1,3-DMP and phenytoin were obtained at 2-3 hr post-administration, probably because the drugs were administered by the oral route as suspensions in 10% aqueous acacia.…”

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confidence: 99%

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N-Demethylation of Methyl and Dimethyl Derivatives of Phenytoin and Their Anticonvulsant Activities in Mice

Wong

Tan

Lee

1988

Japanese Journal of Pharmacology

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Abstract-Anticonvulsant activities of 3-methylphenytoin (3-MP) and 1 ,3 dimethylphenytoin (1,3-DMP) were observed to peak 3 hr after i .p. administration of the drugs dissolved in dimethylsulphoxide (DMSO), while maximal activity was obtained within 15 min with phenytoin. HPLC was employed to monitor the plasma concentrations of all three compounds at various time intervals after injecting 3-MP or 1,3-DMP. In both cases, phenytoin appeared in the plasma, gradually reaching 14-15 /ag/ml in 3 hr. The time course of increase in plasma phenytoin levels correlated with that of anticonvulsant activities. It was also found that 1 ,3 DMP gave rise to a major unidentified metabolite as well as 3-MP and phenytoin . This unidentified metabolite eluted only half a minute in front of 3-MP in the HPLC . Mice injected with high doses of 3-MP (100 mg/kg) in DMSO exhibited severe epileptiform activities. Phenobarbital, diazepam and clonazepam were found to protect against such seizures, but not phenytoin, carbamazepine and valproic acid. This shows that 3-MP is at least a pro-convulsant, taking into account that its effects might have been enhanced by DMSO. Unlike phenytoin, 3-MP lacked the ability to inhibit synaptosomal uptakes of both glutamate and GABA. This difference may be related to the fact that phenytoin, but not 3-MP, possesses potent anticonvulsant activity.Phenytoin (5,5-diphenylhydantoin) is a widely used drug in the treatment of most forms of epilepsy. In laboratory animals, its anticonvulsant activity is characterized by the effectiveness against maximal electroshock seizure (MES) but not pentylenetetrazole induced seizure. The ED50 is approx. 8 mg/kg in mice (1, 2). In our hands, the ED50 is 11 mg/kg (P.T.-H. Wong and S.-F. Tan, un published). Vida et al. (3) reported that two methyl derivatives of phenytoin, 3-methyl phenytoin (3-MP) and 1,3-dimethylpheny toin (1,3-DMP), are effective against MES in mice with ED50 values of about 5 and 50 mg/kg, respectively. Peak activities for 3-MP, 1,3-DMP and phenytoin were obtained at 2-3 hr post-administration, probably because the drugs were administered by the oral route as suspensions in 10% aqueous acacia. It is well known that mephenytoin (3-methyl-5 ethyl 5-phenylhydantoin), a phenytoin ana logue with clinical efficacy, is N-demethylated to an active metabolite 5-ethyl-5-phenyl hydantoin (4). This means that there is a distinct possibility of phenytoin being formed from its methyl derivatives, particularly when there is a considerable time lapse of 2-3 hr between drug administration and the meas urement of anticonvulsant activities. By using a suitable vehicle and route of admin istration to ensure rapid absorption and penetration into the brain, we reevaluated the actions of these phenytoin analogues. Materials and MethodsChemical synthesis: 3-MP was prepared by adding with continuous stirring 2 ml of NaOH (10%) followed by 1 ml of dimethyl sulphate to 10 ml of phenytoin sodium (0.2 g/ml). After standing for 30 min at room temp., the mixture was cooled in an ice ...

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“…The ED50 is approx. 8 mg/kg in mice (1,2). In our hands, the ED50 is 11 mg/kg (P.T.-H. Wong and S.-F. Tan, un published).…”

mentioning

confidence: 57%

mentioning

confidence: 99%

N-Demethylation of Methyl and Dimethyl Derivatives of Phenytoin and Their Anticonvulsant Activities in Mice

Wong

Tan

Lee

1988

Japanese Journal of Pharmacology

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“…IR spectra were measured on a Shimadzu IR 460 spectrometer. 1 H and 13 C NMR spectra were measured with BRUKER DRX-500 AVANCE spectrometer at 500.1 and 125.8 MHz, respectively. The mass spectra were recorded on a Finnigan-Matt 8430 mass spectrometer operating at an ionization potential of 70 eV.…”

Section: Methodsmentioning

confidence: 99%

Triphenylphosphine-Mediated Chemoselective Synthesis of Functionalized Spiro-Imidazol-4-Ones

Yavari

Zabarjad‐Shiraz

2004

Phosphorus, Sulfur, and Silicon and the Related Elements

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“…The hydantoin nucleus containing an active urea moiety is responsible for a variety of biological activities such as antiarrhythmic, antihypertensive, antiviral, antineoplastic, anticonvulsant, antimycobacterial, antiulcer, anti-inflammatory agents, as well as pesticides 3 . Additionally, 2-Thiohydantoin derivatives have been identified as molecules which may interact with a wide range of applications as therapeutics [4][5][6] , as well as fungicides and herbicides 7 .…”

Section: Introductionmentioning

confidence: 99%

One-Pot Multicomponent Synthesis of 2-Azapyrrolizidine Alkaloid Derivatives under Microwave Irradiation

Dabholkar¹,

Jaiswar²,

Krishnan³

et al. 2018

ijcps

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Potential anticonvulsants. 1. 5-Benzylhydantoins

Cited by 70 publications

References 3 publications

N-Demethylation of Methyl and Dimethyl Derivatives of Phenytoin and Their Anticonvulsant Activities in Mice

N-Demethylation of Methyl and Dimethyl Derivatives of Phenytoin and Their Anticonvulsant Activities in Mice

Triphenylphosphine-Mediated Chemoselective Synthesis of Functionalized Spiro-Imidazol-4-Ones

One-Pot Multicomponent Synthesis of 2-Azapyrrolizidine Alkaloid Derivatives under Microwave Irradiation

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