title: Impairment of locomotor activity induced by the novel N-acylhydrazone derivatives LASSBio-785 and LASSBio-786 in mice.
abstract: The N-acylhydrazone (NAH) analogues N-methyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-785) and N-benzyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-786) were prepared from 2-thienylidene 3,4-methylenedioxybenzoylhydrazine (LASSBio-294). The ability of LASSBio-785 and LASSBio-786 to decrease central nervous system activity was investigated in male Swiss mice. LASSBio-785 or LASSBio-786 (30 mg/kg, ip) reduced locomotor activity from 209 ± 26 (control) to 140 ± 18 (P < 0.05) or 146 ± 15 crossings/min (P < 0.05), respectively. LASSBio-785 (15 or 30 mg/kg, iv) also reduced locomotor activity from 200 ± 15 to 116 ± 29 (P < 0.05) or 60 ± 16 crossings/min (P < 0.01), respectively. Likewise, LASSBio-786 (15 or 30 mg/kg, iv) reduced locomotor activity from 200 ± 15 to 127 ± 10 (P < 0.01) or 96 ± 14 crossings/min (P < 0.01), respectively. Pretreatment with flumazenil (20 mg/kg, ip) prevented the locomotor impairment induced by NAH analogues (15 mg/kg, iv), providing evidence that the benzodiazepine (BDZ) receptor is involved. This finding was supported by the structural similarity of NAH analogues to midazolam. However, LASSBio-785 showed weak binding to the BDZ receptor. LASSBio-785 or LASSBio-786 (30 mg/kg, ip, n = 10) increased pentobarbital-induced sleeping time from 42 ± 5 (DMSO) to 66 ± 6 (P < 0.05) or 75 ± 4 min (P < 0.05), respectively. The dose required to achieve 50% hypnosis (HD50) following iv injection of LASSBio-785 or LASSBio-786 was 15.8 or 9.5 mg/kg, respectively. These data suggest that both NAH analogues might be useful for the development of new neuroactive drugs for the treatment of insomnia or for use in conjunction with general anesthesia.
authors.affiliation: Programa de Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil.
authors.forename: G A P
authors.initials: GA
authors.lastname: Silva
authors.forename: A E
authors.initials: AE
authors.lastname: Kummerle
authors.forename: F
authors.initials: F
authors.lastname: Antunes
authors.forename: C A M
authors.initials: CA
authors.lastname: Fraga
authors.forename: E J
authors.initials: EJ
authors.lastname: Barreiro
authors.forename: G
authors.initials: G
authors.lastname: Zapata-Sudo
authors.forename: R T
authors.initials: RT
authors.lastname: Sudo
mesh_terms: D000818:Animals; D006834:Hydrazines / Q000737:chemistry / Q000494:pharmacology*; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D018079:Receptors, GABA / Q000187:drug effects* / Q000502:physiology; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D006834:Hydrazines; D006835:Hydrazones; D006993:Hypnotics and Sedatives; C503362:LASSBio-785; C000594508:N-Benzyl (2-thienylidene) 3,4-methylenedioxybenzoylhydrazine; D018079:Receptors, GABA; D013876:Thiophenes
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