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Synthesis, anticonvulsant, sedative and anxiolytic activities of novel annulated pyrrolo[1,4]benzodiazepines.

Sorra K, Chen CS, Chang CF, Pusuluri S, Mukkanti K, Wu CR, Chuang TH - Int J Mol Sci (2014)

Bottom Line: Four new pentacyclic benzodiazepine derivatives (PBDTs 13-16) were synthesized by conventional thermal heating and microwave-assisted intramolecular cyclocondensation.PBDT 13, a triazolopyrrolo[2,1-c][1,4]benzodiazepin-8-one fused with a thiadiazolone ring, exhibited the best anticonvulsant, sedative and anxiolytic effects in our tests.There was no significant difference in potency between PBDT 13 and diazepam, and we proposed that the action mechanism of PBDT 13 could be similar to that of diazepam via benzodiazepine receptors.

View Article: PubMed Central - PubMed

Affiliation: Medicinal Chemistry Laboratory, Gunapati Venkata Krishnareddy Biosciences Private Limited, Plot No. 28A, Industrial Development Area Nacharam, Hyderabad 500076, India. kumaraswamy.s@gvkbio.com.

ABSTRACT
Four new pentacyclic benzodiazepine derivatives (PBDTs 13-16) were synthesized by conventional thermal heating and microwave-assisted intramolecular cyclocondensation. Their anticonvulsant, sedative and anxiolytic activities were evaluated by drug-induced convulsion models, a pentobarbital-induced hypnotic model and an elevated plus maze in mice. PBDT 13, a triazolopyrrolo[2,1-c][1,4]benzodiazepin-8-one fused with a thiadiazolone ring, exhibited the best anticonvulsant, sedative and anxiolytic effects in our tests. There was no significant difference in potency between PBDT 13 and diazepam, and we proposed that the action mechanism of PBDT 13 could be similar to that of diazepam via benzodiazepine receptors.

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The effects of PBDTs 13–16 (1 mg/kg, ip) or diazepam (1 mg/kg, ip) on the (A) the percentage of open arm entries; (B) the percentage of time spent in open arm entries; (C) the percentage of closed arm entries and (D) the percentage of time spent in the closed arm entries of the elevated pus maze during a 5-min test in male mice. Values are the mean ± SEM, n = 4 mice; *p < 0.05, ***p < 0.001, compared with the vehicle group.
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ijms-15-16500-f003: The effects of PBDTs 13–16 (1 mg/kg, ip) or diazepam (1 mg/kg, ip) on the (A) the percentage of open arm entries; (B) the percentage of time spent in open arm entries; (C) the percentage of closed arm entries and (D) the percentage of time spent in the closed arm entries of the elevated pus maze during a 5-min test in male mice. Values are the mean ± SEM, n = 4 mice; *p < 0.05, ***p < 0.001, compared with the vehicle group.

Mentions: Finally, we evaluated the anxiolytic effects of PBDTs 13–16 by the elevated plus maze. EPM is the most popular test of anxiety and the first-choice test for screening anxiolytic drugs [32]. The anxiolytic effects of PBDTs 13–16 and diazepam on the elevated plus maze are shown in Figure 3. PBDTs 13 and 15 increased the percentage of the time spent in the open arms (***p < 0.001), but only PBDT 13 increased the percentage of the entries into open arms in the elevated plus maze (*p < 0.05). No significant changes in the percentage of the entries into open arms and the time spent in the open arms in the elevated plus maze were observed by the administration of PBDTs 14 and 16. Diazepam at 1 mg/kg also induced a significant increment in the percentage of the entries into open arms and the time spent in the open arms (*p < 0.05, ***p < 0.001). Therefore, we further suggested that only PBDT 13, similar to diazepam, possesses a better anxiolytic effects via benzodiazepine receptors.


Synthesis, anticonvulsant, sedative and anxiolytic activities of novel annulated pyrrolo[1,4]benzodiazepines.

Sorra K, Chen CS, Chang CF, Pusuluri S, Mukkanti K, Wu CR, Chuang TH - Int J Mol Sci (2014)

The effects of PBDTs 13–16 (1 mg/kg, ip) or diazepam (1 mg/kg, ip) on the (A) the percentage of open arm entries; (B) the percentage of time spent in open arm entries; (C) the percentage of closed arm entries and (D) the percentage of time spent in the closed arm entries of the elevated pus maze during a 5-min test in male mice. Values are the mean ± SEM, n = 4 mice; *p < 0.05, ***p < 0.001, compared with the vehicle group.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4200843&req=5

ijms-15-16500-f003: The effects of PBDTs 13–16 (1 mg/kg, ip) or diazepam (1 mg/kg, ip) on the (A) the percentage of open arm entries; (B) the percentage of time spent in open arm entries; (C) the percentage of closed arm entries and (D) the percentage of time spent in the closed arm entries of the elevated pus maze during a 5-min test in male mice. Values are the mean ± SEM, n = 4 mice; *p < 0.05, ***p < 0.001, compared with the vehicle group.
Mentions: Finally, we evaluated the anxiolytic effects of PBDTs 13–16 by the elevated plus maze. EPM is the most popular test of anxiety and the first-choice test for screening anxiolytic drugs [32]. The anxiolytic effects of PBDTs 13–16 and diazepam on the elevated plus maze are shown in Figure 3. PBDTs 13 and 15 increased the percentage of the time spent in the open arms (***p < 0.001), but only PBDT 13 increased the percentage of the entries into open arms in the elevated plus maze (*p < 0.05). No significant changes in the percentage of the entries into open arms and the time spent in the open arms in the elevated plus maze were observed by the administration of PBDTs 14 and 16. Diazepam at 1 mg/kg also induced a significant increment in the percentage of the entries into open arms and the time spent in the open arms (*p < 0.05, ***p < 0.001). Therefore, we further suggested that only PBDT 13, similar to diazepam, possesses a better anxiolytic effects via benzodiazepine receptors.

Bottom Line: Four new pentacyclic benzodiazepine derivatives (PBDTs 13-16) were synthesized by conventional thermal heating and microwave-assisted intramolecular cyclocondensation.PBDT 13, a triazolopyrrolo[2,1-c][1,4]benzodiazepin-8-one fused with a thiadiazolone ring, exhibited the best anticonvulsant, sedative and anxiolytic effects in our tests.There was no significant difference in potency between PBDT 13 and diazepam, and we proposed that the action mechanism of PBDT 13 could be similar to that of diazepam via benzodiazepine receptors.

View Article: PubMed Central - PubMed

Affiliation: Medicinal Chemistry Laboratory, Gunapati Venkata Krishnareddy Biosciences Private Limited, Plot No. 28A, Industrial Development Area Nacharam, Hyderabad 500076, India. kumaraswamy.s@gvkbio.com.

ABSTRACT
Four new pentacyclic benzodiazepine derivatives (PBDTs 13-16) were synthesized by conventional thermal heating and microwave-assisted intramolecular cyclocondensation. Their anticonvulsant, sedative and anxiolytic activities were evaluated by drug-induced convulsion models, a pentobarbital-induced hypnotic model and an elevated plus maze in mice. PBDT 13, a triazolopyrrolo[2,1-c][1,4]benzodiazepin-8-one fused with a thiadiazolone ring, exhibited the best anticonvulsant, sedative and anxiolytic effects in our tests. There was no significant difference in potency between PBDT 13 and diazepam, and we proposed that the action mechanism of PBDT 13 could be similar to that of diazepam via benzodiazepine receptors.

Show MeSH
Related in: MedlinePlus