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Drug Design, Development and Therapy Volume 10, 2016 - Issue
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Original Research

Non-imidazole-based histamine H3 receptor antagonists with anticonvulsant activity in different seizure models in male adult rats

Bassem Sadek1 Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab EmiratesCorrespondence[email protected]
,
Ali Saad1 Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
,
Gniewomir Latacz2 Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland
,
Kamil Kuder2 Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland
,
Agnieszka Olejarz2 Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland
,
Tadeusz Karcz2 Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland
,
Holger Stark3 Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University, Düsseldorf, Germany
&
Katarzyna Kieć-Kononowicz2 Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland
 show all
Pages 3879-3898 | Published online: 25 Nov 2016

Figures & data

Figure 1 Chemical structures, in vitro affinities, and in vivo potencies of previously described H3R ligands PIT (1, Wakix®)Citation22 and DL-77 (2).Citation19,Citation30,Citation72

Notes: aCentral histamine H3R assay in vivo after po administration to mice, n=3.30,59–62 b[125I]Iodoproxyfan binding assay at human H3R stably expressed in CHO-K1 cells, n=3.30,63,64 c[3H]Histamine binding assay performed with cell membrane preparation of Sf9 cells transiently expressing the human histamine H4R and co-expressed with Gαi2 and Gβ1γ2 subunits, n=3.31,65–67 d[3H]Pyrilamine binding assay performed with cell membrane preparation of CHO-hH1R cells stably expressing the human H1R, n=3.Citation68–Citation70
Abbreviations: H3R, H3 receptor; PIT, pitolisant; p.o., peroral.
Figure 1 Chemical structures, in vitro affinities, and in vivo potencies of previously described H3R ligands PIT (1, Wakix®)Citation22 and DL-77 (2).Citation19,Citation30,Citation72

Table 1 Affinities of test compounds 3–14 at hH3R stably expressed in HEK cells

Figure 2 Protective effect of acute systemic injection of H3R ligands 3–14 on MES-induced convulsions in rats.

Notes: (A) The figure shows the protective effects of PHT (10 mg/kg, i.p.), PIT (10 mg/kg, i.p.), and test compounds 3–14 (10 mg/kg, i.p.) on the duration of THLE induced in the MES model in rats. Values are mean ± SEM (n=7). *P<0.005 vs the saline-treated group. **P<0.001 (B) 1: Dose-dependent effect of H3R ligand 14 (5, 10, and 20 mg/kg, i.p.) on duration of THLE induced in the MES model in rats; 2: Effect of PYR (10 mg/kg, i.p.) and ZOL (10 mg/kg, i.p.) pretreatment on the protection provided by H3R 14 (10 mg/kg, i.p.) against MES-induced convulsions. Each value represents mean ± SEM (n=7). *P<0.05 vs (saline)-treated group. **P<0.001 vs (saline)-treated group. #P<0.05 vs (5 mg)-treated group.
Abbreviations: H3R, H3 receptor; MES, maximal electroshock; PHT, phenytoin; PIT, pitolisant; THLE, tonic hind limb extension; PYR, pyrilamine; ZOL, zolantidine; SEM, standard error of the mean; SAL, saline.
Figure 2 Protective effect of acute systemic injection of H3R ligands 3–14 on MES-induced convulsions in rats.

Figure 3 Protective effect of H3R ligands 3–14 pretreatment on PTZ-induced convulsions in rats.

Notes: (A) VPA (100 mg/kg, i.p.), PIT (10 mg/kg, i.p.), and compounds 3–14 (10 mg/kg, i.p.) were injected 30 min before PTZ (60 mg/kg, i.p.) treatments. Effects shown are expressed as score of seizures after 10, 20, and 30 min of PTZ injection. Data are expressed as the mean ± SEM (n=7). *P<0.05 vs the (PTZ–saline)-treated group. #Full protection. (B) Dose-dependent effect of H3R ligands 4 and 6 (A, B, and C in a dose of 5, 10, and 20 mg/kg, i.p. respectively) on the convulsion score induced in the PTZ model in rats. Effect of PYR (10 mg/kg, i.p.) and ZOL (10 mg/kg) pretreatment on the protection provided by H3R ligand 4 (10 mg/kg, i.p.) against PTZ-induced convulsions. Each value represents mean ± SEM (n=7). *P<0.05 vs (PTZ–saline)-treated group. #Full protection.
Abbreviations: H3R, H3 receptor; PTZ, pentylenetetrazole; VPA, valproic acid; PIT, pitolisant; SEM, standard error of the mean; PYR, pyrilamine; ZOL, zolantidine.
Figure 3 Protective effect of H3R ligands 3–14 pretreatment on PTZ-induced convulsions in rats.

Figure 4 Protective effect of H3R ligands 3–14 pretreatment on STR-induced convulsions in rats.

Notes: (A) VPA (300 mg/kg, i.p.), PIT (10 mg/kg, i.p.), and compounds 3–14 (10 mg/kg, i.p.) were injected 30 min before STR (3.5 mg/kg, i.p.) treatments. Values are expressed as the mean ± SEM (n=7). *P<0.001 vs (STR–saline)-treated group. #Full protection. (B) Dose-dependent effect of H3R ligand 14 (A, B, and C in a dose of 5, 10, and 20 mg/kg, i.p., respectively) on the convulsion score induced in the STR model in rats, and effect of PYR (10 mg/kg, i.p.) and ZOL (10 mg/kg) pretreatment on the protection provided by H3R ligand 14 (10 mg/kg, i.p.) against STR-induced convulsions. Each value represents mean ± SEM (n=7). *P<0.05 vs (PTZ–saline)-treated group. **P<0.001. #Full protection.
Abbreviations: H3R, H3 receptor; STR, strychnine; VPA, valproic acid; PIT, pitolisant; SEM, standard error of the mean; PYR, pyrilamine; ZOL, zolantidine; PTZ, pentyl-enetetrazole.
Figure 4 Protective effect of H3R ligands 3–14 pretreatment on STR-induced convulsions in rats.

Table 2 Practical (RM0) and theoretical lipophilicity values for the series of described compounds

Table 3 The number of metabolites of selected H3R ligands and their molecular masses

Figure 5 The plot of MetaSite predictions for sites of metabolism of compounds 2, 4, 6, 7, and 14.

Abbreviations: UPLC, ultra-performance liquid chromatography; HLMs, human liver microsomes.
Figure 5 The plot of MetaSite predictions for sites of metabolism of compounds 2, 4, 6, 7, and 14.

Figure 6 The UPLC spectrum after 120 min reaction of 2, 4, 6, 7, and 14 with HLMs.

Notes: The darker color of the marked functional group indicates its higher probability to be involved in the metabolic pathway. The blue circle marks the site of H3R ligand involved in metabolism with the highest probability calculated by MetaSite method.
Abbreviation: H3R, H3 receptor.
Figure 6 The UPLC spectrum after 120 min reaction of 2, 4, 6, 7, and 14 with HLMs.

Figure 7 (A) Ion fragment analysis and probable structure of the main metabolite M1 of compound 2. (B) Ion fragment analysis and probable structure of the main metabolite M1 of compound 4. (C) Ion fragment analysis and probable structure of the main metabolite M1 of compound 6. (D) Ion fragment analysis and probable structure of the main metabolite M1 of compound 7. (E) Ion fragment analysis and two proposed structures of the main metabolite M1 of compound 14.

Figure 7 (A) Ion fragment analysis and probable structure of the main metabolite M1 of compound 2. (B) Ion fragment analysis and probable structure of the main metabolite M1 of compound 4. (C) Ion fragment analysis and probable structure of the main metabolite M1 of compound 6. (D) Ion fragment analysis and probable structure of the main metabolite M1 of compound 7. (E) Ion fragment analysis and two proposed structures of the main metabolite M1 of compound 14.
Figure 7 (A) Ion fragment analysis and probable structure of the main metabolite M1 of compound 2. (B) Ion fragment analysis and probable structure of the main metabolite M1 of compound 4. (C) Ion fragment analysis and probable structure of the main metabolite M1 of compound 6. (D) Ion fragment analysis and probable structure of the main metabolite M1 of compound 7. (E) Ion fragment analysis and two proposed structures of the main metabolite M1 of compound 14.
Figure 7 (A) Ion fragment analysis and probable structure of the main metabolite M1 of compound 2. (B) Ion fragment analysis and probable structure of the main metabolite M1 of compound 4. (C) Ion fragment analysis and probable structure of the main metabolite M1 of compound 6. (D) Ion fragment analysis and probable structure of the main metabolite M1 of compound 7. (E) Ion fragment analysis and two proposed structures of the main metabolite M1 of compound 14.

Figure 8 (A) Effect of KE and compounds 2, 4, 6, 7, and 14 on CYP3A4 activity. (B) Effect of QD and compounds 1, 2, 4, 6, 7, and 14 on CYP2D6 activity. (C) Activity of the reference DX and compounds 2, 4, 6, 7, and 14 against HEK-293 cell line.

Abbreviations: KE, ketoconazole; CYP, cytochrome P450; QD, quinidine; DX, doxorubicin; HEK, human embryonic kidney.
Figure 8 (A) Effect of KE and compounds 2, 4, 6, 7, and 14 on CYP3A4 activity. (B) Effect of QD and compounds 1, 2, 4, 6, 7, and 14 on CYP2D6 activity. (C) Activity of the reference DX and compounds 2, 4, 6, 7, and 14 against HEK-293 cell line.

Figure 9 Increase of histidine prototrophy revertants over baseline for Salmonella typhimurium strain TA98, exposed to H3R ligands (1 or 10 µM) or reference mutagen NQNO (0.5 µM).

Note: Assay was performed in triplicates.
Abbreviations: H3R, H3 receptor; NQNO, nonyl-4-hydroxyquinoline-N-oxide.
Figure 9 Increase of histidine prototrophy revertants over baseline for Salmonella typhimurium strain TA98, exposed to H3R ligands (1 or 10 µM) or reference mutagen NQNO (0.5 µM).

Scheme 1 General structure of tested compounds (3–14).

Scheme 1 General structure of tested compounds (3–14).

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