Anticonvulsant effects of isomeric nonimidazole histamine H₃ receptor antagonists

Figures & data

Figure 1 Structures of considered AEDs and of newly designed final compounds 1–6.

Abbreviation: AEDs, antiepileptic drugs.

Table 1 In vitro affinities at hH₁Rs, hH₂Rs, and hH₄Rs and in vivo anticonvulsant effects of final compounds 1–6

Compound	Structure	Ki(hH3R)a(nM)	Ki(hH4R)b(nM)	Ki(hH1R)c(nM)	In vivo anticonvulsant effect
					MES	PTZ	STR
1		43.26±4.09	>100,000	>10,000	−	−	−
2		8.55±2.35	>100,000	>10,000	+	−	+
3		5.35±0.67	>10,000	1,986±149	++	−	−
4		20.91±4.81	>100,000	3,215±1,716	−	++	−
5d		6.15±1.19	>10,000	6,310±986	−	−	−
6		579±93	>100,000	6,145±562	−	++	−
PIT		11.69±2.47e	<10,000	>10,000	+	−	−

Notes:

a [³H]N^α-Methylhistamine binding assay performed with cell membrane preparation of HEK cells stably expressing the human H₃R, and assays were conducted at least in three to five experiments in triplicates with seven appropriate concentrations in the range of 0.01 nM–10 µM of the respective test compound.

b [³H]Histamine binding assay performed with cell membrane preparation of Sf9 cells transiently expressing the human histamine H₄R and coexpressed with G_αi2 and G_β1γ2 subunits (n=2).

c [³H] Pyrilamine binding assay performed with cell membrane preparation of CHO cells stably expressing the human H₁R (n=2).

d Synthesis of compound 5.³¹

e Values for PIT.²⁵ −, No protection; +, moderate protective effect; ++, high protective effect.

Abbreviations: MES, maximal electroshock; PTZ, pentylenetetrazole; STR, strychnine; PIT, pitolisant; HEK, human embryonic kidney; CHO, Chinese hamster ovary.

Figure 2 Protective effect of acute systemic injection of H₃R ligands 1–6 on MES-induced convulsions in rats.

Notes: The figure shows the protective effects of PHT (10 mg/kg, IP), PIT, (10 mg/kg, IP), and test compounds 1–6 (10 mg/kg, IP) on the duration of THLE induced in the MES model in rats. Values are mean ± SEM (n=7). *P<0.05 vs the saline-treated group. **P<0.001 vs (saline)-, (PIT)-, or (2)-treated group.
Abbreviations: PHT, phenytoin; PIT, pitolisant; THLE, tonic hind limb extension; MES, maximal electroshock; IP, intraperitoneally; SEM, standard error of the mean; s, seconds.

Figure 3 Dose-dependent protective effect of H₃R ligand 3 against MES-induced convulsions.

Notes: Effect of H₃R ligand 3 on duration of THLE induced in MES model in rats. Each value represents mean ± SEM (n=7). *P<0.001 vs (saline)-treated group. **P<0.001 vs (5 mg)-treated group.
Abbreviations: THLE, tonic hind limb extension; MES, maximal electroshock; SEM, standard error of the mean; s, seconds.

Figure 4 Effect of RAMH (10 mg/kg, IP) pretreatment on the protection by H₃R ligand 3 (10 mg/kg, IP) on MES-induced convulsions.

Notes: Effects shown are expressed as the duration of THLE induced in the MES model in rats. Values are mean ± SEM (n=7). *P<0.001 vs (saline)-treated group.
Abbreviations: THLE, tonic hind limb extension; MES, maximal electroshock; RAMH, R-(α)-methyl-histamine; IP, intraperitoneally; SEM, standard error of the mean; s, seconds.

Figure 5 Protective effect of H₃R ligands 1–6 pretreatment on PTZ-induced convulsions in rats.

Notes: Valproic acid (100 mg/kg, IP), PIT (10 mg/kg, IP), and compounds 1–6 (10 mg/kg, IP) were injected 30 minutes before PTZ (60 mg/kg, IP) treatments. Values are as the mean ± SEM (n=7). *P<0.05 vs the (PTZ-saline)-treated group. **Full protection.
Abbreviations: VPA, valproic acid; PIT, pitolisant; PTZ, pentylenetetrazole; IP, intraperitoneally; SEM, standard error of the mean.

Figure 6 Dose-dependent protective effect of H₃R ligands 2, 4, and 5 against PTZ-induced convulsions.

Notes: Effect of 5, 10, and 15 mg/kg of 2, 4, and 5 on the convulsion score induced in PTZ model in rats. Each value represents mean ± SEM (n=6). *P<0.05 vs the (PTZ-saline)-treated group. **Full protection.
Abbreviations: PTZ, pentylenetetrazole; SEM, standard error of the mean.

Figure 7 Effect of RAMH (10 mg/kg, IP) pretreatment on the protection by H₃R ligand 4 (10 mg/kg, IP) on PTZ-induced convulsions in rats.

Notes: Effect shown is on the convulsion score induced in PTZ model in rats. Each value represents mean ± SEM (n=7). *Full protection.
Abbreviations: PTZ, pentylenetetrazole; RAMH, R-(α)-methyl-histamine; IP, intraperi-toneally.

Figure 8 Protective effect of H₃R ligands 1–6 pretreatment on STR-induced convulsions in rats.

Notes: VPA (300 mg/kg, IP), PIT (10 mg/kg, IP), and compounds 1–6 (10 mg/kg, IP) were injected 30 minutes before STR (3.5 mg/kg, IP) treatments. Values are represented as mean ± SEM (n=7). *P<0.05 vs (STR-saline)-treated group. **P<0.001 vs (STR-saline)-treated group. ^#Full protection.
Abbreviations: STR, strychnine; VPA, valproic acid; PIT, pitolisant; IP, intraperitoneally; SEM, standard error of the mean.

Scheme 1 Synthesis of precursors P1–P9 and final H₃R ligands 1–6.

Notes: Reagents and conditions: (i) 1. K₂CO₃, KI, acetone, reflux, 3 days; 2. HCl, 2-propanol; 79%. (ii) SOCl₂, toluene, 0°C→60°C, 3 hours; quantitative conversion. (iii) 4-Hydroxybenzaldehyde, K₂CO₃, acetonitrile, reflux 16 hours. (iv) 1. (S)-2-Aminopropaneamide for 1 and (R)-2-aminopropaneamide for 2, ethanol, stirring at RT, 16 hours; 2. NaBH₄, 0°C/RT, 15 minutes, 51% for 1 and 52% for 2. (v) 4-(Hydroxymethyl)phenol, K₂CO₃, KI, acetone, reflux, 2–3 days; 52%. (vi) SOCl₂, toluene, 0°C→60°C, 3 hours; quantitative conversion. (vii) 4-Hydroxybenzaldehyde, K₂CO₃, acetonitrile, reflux 16 hours. (viii) 1. (R)-2-Aminopropaneamide for 3 and (S)-2-aminopropaneamide for 4, ethanol, stirring at RT, 16 hours; 2. NaBH₄, 0°C/RT, 15 minutes, 77% for 3 and 97% for 4. (ix) As previously described for 5 by Sadek et al.³¹ (x) 1-(4-Hydroxyphenyl)-2-phenylethanone, K₂CO₃, KI, acetone, reflux, 2–3 days; 97%. (xi) CuBr₂, solvent mixture DMSO and abs. ethylacetate 1:1, argon atmosphere, 2 days, 60°C.³⁵ (xii) CuBr₂, solvent mixture DMSO and abs. ethylacetate 1:1, argon atmosphere, 2 days, 60°C.³⁵ (xiii) 1-(3-Chloropropyl)piperidine K₂CO₃, acetonitrile, reflux 16 hours. (xiv) Urea, NaOH 30% and EtOH, microwave 10 minutes, 120°C, 40% for 6.
Abbreviation: RT, room temperature.

SadekBSchwedJSSubramanianDNon-imidazole histamine H3 receptor ligands incorporating antiepileptic moietiesEur J Med Chem20147726927924650714

 PubMed Web of Science ®Google Scholar

SanderKKottkeTStarkHHistamine H3 receptor antagonists go to clinicsBiol Pharm Bull200831122163218119043195

 PubMed Web of Science ®Google Scholar

BaekJBHarrisFWDevelopment of an improved synthetic route to an AB phenylquinoxaline monomerJ Polym Sci A Polym Chem2005434801814

 Web of Science ®Google Scholar