TY - JOUR
T1 - Non-imidazole histamine H3 receptor ligands incorporating antiepileptic moieties
AU - Sadek, Bassem
AU - Schwed, Johannes Stephan
AU - Subramanian, Dhanasekaran
AU - Weizel, Lilia
AU - Walter, Miriam
AU - Adem, Abdu
AU - Stark, Holger
N1 - Funding Information:
Supported by Faculty Grant NP/13/17 of College of Medicine and Health Sciences, UAE University , and We greatly thank Prof. J.-C. Schwartz (Bioprojet, Saint-Grégoire, France) for providing HEK-293 cells stably expressing the recombinant human histamine H 3 receptor. The CHO-K1 cells stably expressing the human histamine H 1 receptor were generously gifted by Prof. H. Timmermann and Prof. R. Leurs (Amsterdam, The Netherlands). We grateful thank Prof. R. Seifert (Hannover, Germany) for providing Sf9 cells and baculovirus stock solutions encoding for the human histamine H 4 receptor and G-protein G αi2 and G β1γ2 subunits. The authors would, also, like to acknowledge Mr. Mohamed Shafiullah for his technical assistance and Professor Keith Bagnall for his critical and careful proofreading. Support for this work has been kindly given to HS by the EU COST Actions BM0806, BM1007, CM1103, and CM1207 as well as the Hesse LOEWE Schwerpunkte Fh-TMP, OSF and NEFF, the Else KrönerStiftung, TRIP and the Deutsches Konsortium für Translationale Krebsforschung, DKTK.
PY - 2014/4/22
Y1 - 2014/4/22
N2 - A small series of histamine H3 receptor (H3R) ligands (1-5) incorporating different antiepileptic structural motifs has been newly synthesized. All compounds exhibited moderate to high in vitro hH3R affinities up to a sub-nanomolar concentration range with pKi values in the range of 6.25-9.62 with varying preferences for this receptor subtype. The compounds (1-5) were further investigated in vivo on anticonvulsant effects against maximum electroshock (MES)-induced and pentylenetetrazole (PTZ)-kindled convulsions in rats having phenytoin (PHT) as the reference antiepileptic drug (AED). Surprisingly, animals pretreated with 1 mg/kg, i.p. of 5,5-diphenyl-3-(3-(piperidin-1-yl)propyl)imidazolidine-2,4-dione (4) were only moderately protected and no protection was observed for compounds 1-3 and 5 in three different doses (1 mg, 5 mg, and 10 mg/kg i.p.). Compound 4 (1 mg/kg, i.p.) failed to modify PTZ-kindled convulsion. However, a dose of 10 mg/kg significantly reduced convulsions in both models. In contrast, 5,5-diphenyl-3-(4-(3-(piperidin-1-yl)propoxy)benzyl)imidazolidine-2,4-dione (5) (1, 5, and 10 mg/kg, i.p.) showed proconvulsant effects in the MES model with further confirmation of these results in the PTZ model as no protection was observed against convulsion in the doses tested (1 and 10 mg/kg). In addition, compound 4 (10 mg/kg, i.p.) significantly prolonged myoclonic latency time and shortened total convulsion duration when compared to control, PHT or standard H3R inverse agonist/antagonist pitolisant (PIT). Our results showed that H3R pharmacophores could successfully be structurally combined to antiepileptic moieties, especially phenytoin partial structures, maintaining the H3R affinity. However, the new derivatives for multiple-target approaches in epilepsy models are complex and show that pharmacophore elements are not easily pharmacologically combinable.
AB - A small series of histamine H3 receptor (H3R) ligands (1-5) incorporating different antiepileptic structural motifs has been newly synthesized. All compounds exhibited moderate to high in vitro hH3R affinities up to a sub-nanomolar concentration range with pKi values in the range of 6.25-9.62 with varying preferences for this receptor subtype. The compounds (1-5) were further investigated in vivo on anticonvulsant effects against maximum electroshock (MES)-induced and pentylenetetrazole (PTZ)-kindled convulsions in rats having phenytoin (PHT) as the reference antiepileptic drug (AED). Surprisingly, animals pretreated with 1 mg/kg, i.p. of 5,5-diphenyl-3-(3-(piperidin-1-yl)propyl)imidazolidine-2,4-dione (4) were only moderately protected and no protection was observed for compounds 1-3 and 5 in three different doses (1 mg, 5 mg, and 10 mg/kg i.p.). Compound 4 (1 mg/kg, i.p.) failed to modify PTZ-kindled convulsion. However, a dose of 10 mg/kg significantly reduced convulsions in both models. In contrast, 5,5-diphenyl-3-(4-(3-(piperidin-1-yl)propoxy)benzyl)imidazolidine-2,4-dione (5) (1, 5, and 10 mg/kg, i.p.) showed proconvulsant effects in the MES model with further confirmation of these results in the PTZ model as no protection was observed against convulsion in the doses tested (1 and 10 mg/kg). In addition, compound 4 (10 mg/kg, i.p.) significantly prolonged myoclonic latency time and shortened total convulsion duration when compared to control, PHT or standard H3R inverse agonist/antagonist pitolisant (PIT). Our results showed that H3R pharmacophores could successfully be structurally combined to antiepileptic moieties, especially phenytoin partial structures, maintaining the H3R affinity. However, the new derivatives for multiple-target approaches in epilepsy models are complex and show that pharmacophore elements are not easily pharmacologically combinable.
KW - Anticonvulsant activity
KW - Convulsion
KW - Epilepsy
KW - GPCR
KW - Histamine
KW - Pharmacophore elements
KW - Phenytoin
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U2 - 10.1016/j.ejmech.2014.03.014
DO - 10.1016/j.ejmech.2014.03.014
M3 - Article
C2 - 24650714
AN - SCOPUS:84896521356
SN - 0223-5234
VL - 77
SP - 269
EP - 279
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -