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Abstract: 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. [Copyright &y& Elsevier]

A series of twenty new chlorophenoxyalkylamine derivatives ( 9 – 28 ) was synthesized and evaluated on their binding properties at the human histamine H 3 receptor (hH 3 R). The spacer alkyl chain contained five to seven carbon atoms. The highest affinities have shown the 4-chloro substituted derivatives 10 and 25 ( K i = 133 and 128 nM, respectively) classified as antagonists in cAMP accumulation assay (EC 50 = 72 and 75 nM, respectively). Synthesized compounds were also evaluated for anticonvulsant activity in Antiepileptic Screening Program (ASP) at National Institute of Neurological Disorders and Stroke (USA). Two compounds (4-chloro substituted derivatives: 20 and 26 ) were the most promising and showed in the MES seizure model in rats (after ip administration) ED 50 values of 14 mg/kg and 13.18 mg/kg, respectively. Protective indexes (PI = TD 50 /ED 50 ) were 3.2 for 20 and 3.8 for 26 . Moreover, molecular modeling and docking studies were undertaken to explain affinity at hH 3 R of target compounds, and the experimentally and in silico estimation of properties like lipophilicity and metabolism was performed. Antiproliferative effects have been also investigated in vitro for selected compounds ( 10 and 25 ). These compounds neither possessed significant antiproliferative and antitumor activity, nor modulated CYP3A4 activity up to concentration of 10 μM. [ABSTRACT FROM AUTHOR]

Within the constantly growing number of histamine H 4 (H 4 R) receptor ligands there is a large group of azine derivatives. A series of novel compounds in the group of 4-methylpiperazine-1,3,5-triazine-2-amines were designed and obtained. Considered structures were modified at the triazine 6-position by introduction of variously substituted arylethenyl moieties. Their affinities to histamine H 4 receptors were evaluated in radioligand binding assays with use of Sf 9 cells, transiently expressing human H 4 R. Pharmacological studies results allowed to identify 4-[( E )-2-(3-chlorophenyl)ethenyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine ( K i = 253 nM) as the most potent compound in the present series. [ABSTRACT FROM AUTHOR]

The histamine H 3 receptor (H 3 R) plays a role in cognitive and memory processes and is involved in different neurological disorders, including Alzheimer's disease, schizophrenia, and narcolepsy. Therefore, several hH 3 R antagonists/inverse agonists entered clinical phases for a broad spectrum of mainly centrally occurring diseases. However, many other promising candidates failed due to their pharmacokinetic profile, mostly because of their strong lipophilicity accompanied with low solubility. Analysis of previous potential H 3 R selective antagonists/inverse agonists, e.g. pitolisant, revealed promising results concerning physicochemical properties and drug-likeness. Herein, a series of new hH 3 R ligands 8 – 20 consisting of piperidin-1-yl or piperidin-1-yl-propoxyphenyl coupled to different uracil, thymine, and 5,6-dimethyluracil related moieties, were synthesized, evaluated on their binding properties at the hH 3 R and the estimation of different physicochemical and drug-likeness properties. Due to the coupling to various positions at pyrimidine-2,4-(1 H ,3 H )-dione, affinity at hH 3 Rs and drug-likeness parameters have been improved. For instance, compound 9 showed in addition to high affinity at the hH 3 R (p K i (hH 3 R) = 8.14) clog S , clog P , LE, LipE, and drug-likeness score values of −4.36, 3.47, 0.34, 4.63, and 1.54, respectively. Also, the methyl substituted analog 17 (p K i (hH 3 R) = 8.15) revealed LE, LipE and drug-likeness score values of −3.29, 2.47, 0.49, 5.52, and 1.76, respectively. [ABSTRACT FROM AUTHOR]