Non-imidazole histamine H₃ receptor ligands incorporating antiepileptic moieties

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 pK_i 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.