Histamine H₃ receptor is constitutively active G_i - protein coupled receptor mostly expressed in central nervous system (CNS), and described as a presynaptically located auto- and heteroreceptor. Blockade of this receptor leads to increased levels of histamine and other neurotransmitters such as: Ach, NA, 5-HT in CNS. Therefore histamine H₃ receptor antagonists may provide novel therapies for treating such CNS diseases as: Alzheimer disease, ADHD, dementia, epilepsy, obesity [1].

First known histamine H₃ receptor antagonists contained imidazole group, which could cause a number of side effects mostly because of cytochrome P₄₅₀ interactions. On the other hand imidazole derivatives may tend to have low bioavailability. Among other proposed, piperazine moiety has been shown to be a suitable bioisosteric replacement of an imidazole moiety. Since prior researches described mainly 4-N-acylated piperazine derivatives of Ciproxifan [2], compounds (Fig. 1) were designed.

Fig.1
The aim of this work was to synthesize (un)substituted 4-N-benzoyl- or aryl(alkyl)-piperazine-1-N-alkyl derivatives (Fig.1) to study the influence of 4-N-piperazine substituents, alkyl chain length and (cyclo)alkyl or arylalkyl lipohilic residue on histamine H₃ receptor activity. Compounds were obtained with microwave oven method, using proper (un)substituted N-piperazinepropan-, or ethan-1-ol derivatives as starting material and via modified Williamson synthesis in KOH/DMSO system.

The novel compounds were evaluated for the histamine H₃ receptor activity in vitro in a binding assay for the human histamine H₃ receptor stably expressed in CHO-K1 cells. Two of the tested compounds showed good antagonist activity at the histamine H₃ receptor.

For the series of compounds physicochemical properties such as lipophilicity by means of logP values and distribution coefficient (logD) were predicted using computer programs [3]. As there is a strong need to describe the ADME parameters for the compounds in the early stages of research, for the representative compounds metabolites were predicted using the program METEOR 6.0.0. [4].

[1] Stark, H. et al. Mini Rev. Med. Chem. 2004, 4, 965-977; Cowart, M. et al. Mini Rev. Med. Chem. 2004, 4, 979-992

[2] Esbenshade, T. A. et al. J. Pharm. Exp. Ther. 2003, 305, 887-896

[3] PALLAS ver. 3.1 demo, CompuDrug; CAChe ProjectLeader 6.1, Fujitsu Ltd.;

[4] METEOR ver. 6.0.0, Lhasa Ltd

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