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Research Paper

Design, synthesis, and anticonvulsant effects evaluation of nonimidazole histamine H3 receptor antagonists/inverse agonists containing triazole moiety

, , , , &
Pages 1310-1321 | Received 07 Feb 2020, Accepted 19 May 2020, Published online: 12 Jun 2020

Figures & data

Figure 1. Structures of histamine H3 receptor ligands with anticonvulsant activity, triazole derivatives with anticonvulsant activity and target compounds 3a-3q designed.

Figure 1. Structures of histamine H3 receptor ligands with anticonvulsant activity, triazole derivatives with anticonvulsant activity and target compounds 3a-3q designed.

Scheme 1. The synthesis route and conditions for the preparation of compounds 3a-3j.

Scheme 1. The synthesis route and conditions for the preparation of compounds 3a-3j.

Scheme 2. The synthesis route and conditions for the preparation of compounds 3k-3q.

Scheme 2. The synthesis route and conditions for the preparation of compounds 3k-3q.

Table 1. H3R antagonistic activity of compounds 3a-3q.

Figure 2. Effects of compounds 3a, 3c, 3h, 3k, 3l, and 3m on the level of intracellular cAMP administrated alone.

Figure 2. Effects of compounds 3a, 3c, 3h, 3k, 3l, and 3m on the level of intracellular cAMP administrated alone.

Figure 3. The H3R inverse agonistic activity (EC50, μM) of Pitolisant and compound 3m.

Figure 3. The H3R inverse agonistic activity (EC50, μM) of Pitolisant and compound 3m.

Figure 4. The predicted configurations for PIT (A), 3h (B) and 3m (C) binding with H3R, and their overlying pattern (D).

Figure 4. The predicted configurations for PIT (A), 3h (B) and 3m (C) binding with H3R, and their overlying pattern (D).

Figure 5. Effects of H3R antagonists/inverse agonists 3a-3q (10 mg/kg, i.p.), PIT (10 mg/kg, i.p.) and anticonvulsant drug VPA (300 mg/kg, i.p.) against MES-induced convulsions. Protection for mice was defined as the reduction or abolition of the tonic hind limb extension (THLE) in MES model. Results are showed as mean ± SEM with seven animals in each group. Values are considered significant at *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 as compared to saline-treated group.

Figure 5. Effects of H3R antagonists/inverse agonists 3a-3q (10 mg/kg, i.p.), PIT (10 mg/kg, i.p.) and anticonvulsant drug VPA (300 mg/kg, i.p.) against MES-induced convulsions. Protection for mice was defined as the reduction or abolition of the tonic hind limb extension (THLE) in MES model. Results are showed as mean ± SEM with seven animals in each group. Values are considered significant at *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 as compared to saline-treated group.

Figure 6. Effects of compounds 3a-3q (10 mg/kg, i.p.), and reference drug PIT (10 mg/kg, i.p.) and VPA (300 mg/kg, i.p.) against PTZ-induced convulsions. Results are showed as mean ± SEM of seven mice in each group. & represent full protection.

Figure 6. Effects of compounds 3a-3q (10 mg/kg, i.p.), and reference drug PIT (10 mg/kg, i.p.) and VPA (300 mg/kg, i.p.) against PTZ-induced convulsions. Results are showed as mean ± SEM of seven mice in each group. & represent full protection.

Figure 7. Protective effects of compound 3m and reference drug PIT against MES-induced convulsions in different doses. Protection in the test was defined as the reduction or abolition of the THLE in mice. Results were showed as mean ± SEM with seven animals in each group. Values are considered significant at *p < 0.05, **p < 0.01, ***p < 0.001 when compared to saline-treated group. &PIT, at 20 mg/kg dose, fully abrogate the THLE for all the tested mice.

Figure 7. Protective effects of compound 3m and reference drug PIT against MES-induced convulsions in different doses. Protection in the test was defined as the reduction or abolition of the THLE in mice. Results were showed as mean ± SEM with seven animals in each group. Values are considered significant at *p < 0.05, **p < 0.01, ***p < 0.001 when compared to saline-treated group. &PIT, at 20 mg/kg dose, fully abrogate the THLE for all the tested mice.

Figure 8. Protective effects of compound 3m (10 mg/kg, i.p.) against MES-induced convulsions when pre-treatment of RAMH (10 mg/kg, i.p.). Protection in the test was defined as the reduction or abolition of the THLE in mice. Results are showed as mean ± SEM with seven animals in each group. Values are considered significant at *p < 0.01 as compared to saline-treated group, and #p < 0.01 as compared to 3m + RAMH treated group.

Figure 8. Protective effects of compound 3m (10 mg/kg, i.p.) against MES-induced convulsions when pre-treatment of RAMH (10 mg/kg, i.p.). Protection in the test was defined as the reduction or abolition of the THLE in mice. Results are showed as mean ± SEM with seven animals in each group. Values are considered significant at *p < 0.01 as compared to saline-treated group, and #p < 0.01 as compared to 3m + RAMH treated group.