Relationship between the brain levels and the anticonvulsant activity of denzimol after its acute and repeated administration to mice

Abbiati, G.; Restelli, G; Schiavi, Sara; Ceserani, R.; Testa, Rodolfo

doi:10.1016/0031-6989(87)90005-1

Cited by 1 publication

(2 citation statements)

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“…At this stage we felt that variation in the "amino acidic" part of the molecule (B, Figure 1) could give us the most relevant information. Replacement with different R-amino amide derivatives for the glycinamide part of 6 enabled us with several potent anticonvulsants (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36), Table 1). The alanine (19-22) and serine (23-25) derivatives were both potent and boasted high therapeutic indexes (TIs) when compared with classical and new-generation anticonvulsants.…”

Section: Resultsmentioning

confidence: 99%

“…Briefly, an electrical stimulus sufficient to produce a hindlimb tonic extensor response in at least 97% of control animals was delivered using an Ugo Basile electroconvulsive generator (model ECT UNIT 7801). The stimulus was delivered intra-aurally through clip electrodes in both rats (0.2 s of a 160-mA shock, with a pulse train of 60 Hz having a pulse duration of 0.4 ms 19 ) and mice (0.7 s of a 28-mA shock, with a pulse train of 80 Hz having a pulse duration of 0.4 ms 20 ). The acute effects of compounds administered 60 min orally (po) or 30 min intraperitoneally (ip) before MES induction were examined.…”

Section: Methodsmentioning

confidence: 99%

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Synthesis and Anticonvulsant Activity of a New Class of 2-[(Arylalkyl)amino]alkanamide Derivatives

et al. 1998

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Although most epilepsies are adequately treated by conventional antiepileptic therapy, there remains an unfulfilled need for safer and more effective anticonvulsant agents. Starting from milacemide, a weak anticonvulsant, and trying to elucidate its mechanism of action, we discovered a structurally novel class of potent and preclinically safe anticonvulsants. Here we report the structure-activity relationship (SAR) study within this series of compounds. Different parts of the structural lead 2-[[4-(3-chlorobenzoxy)benzyl]amino]acetamide (6) were thus varied (Figure 1), and many potent anticonvulsants were found. As an outcome of this study, 57 ((S)-2-[[4-(3-fluorobenzoxy)benzyl]amino]propanamide methanesulfonate, PNU-151774E) emerged as a promising candidate for further development for its potent anticonvulsant activity and outstanding therapeutic indexes (TIs) in different animal tests.

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