Dataset Information

Design, synthesis, and in vitro and in vivo characterization of 1-{4-[4-(substituted)piperazin-1-yl]butyl}guanidines and their piperidine analogues as histamine H3 receptor antagonists.

ABSTRACT: Previously, we have shown that 1-substituted-[4-(7-phenoxyheptylpiperazin-1-yl)butyl]guanidine with electron withdrawing substituents at position 4 in the benzyl moiety exhibits high in vitro affinities toward the guinea pig jejunal histamine H3 receptor with pA 2 ranging from 8.49 to 8.43. Here, we present data on the impact of replacement of the piperazine scaffold by the piperidine ring (compounds 2a and 2b), moving benzyl- and 4-trifluoromethylbenzyl substituents from position 1 to 3 of the guanidine moiety (compounds 2c and 2d), which decreases the guanidine basicity (compound 2e), and the influence of individual synthons (compounds 2f-h), present in the lead compounds 1b and 1c, on the antagonistic activity against the histamine H3 receptor. Additionally, the most active compounds 1a, 1c, and 1d were evaluated for their affinity to the rat histamine H3 receptor and the human histamine H3 and H4 receptors. It was also shown that compounds 1a, 1c and 1d, given parenterally for five days, reduced the food intake of rats and did not influence the brain histamine or noradrenaline concentrations; however, significantly reduced serotonin and dopamine concentrations were found in rats administered with compounds 1a and 1c, respectively.

SUBMITTER: Staszewski M

PROVIDER: S-EPMC6390473 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Design, synthesis, and in vitro and in vivo characterization of 1-{4-[4-(substituted)piperazin-1-yl]butyl}guanidines and their piperidine analogues as histamine H3 receptor antagonists.

Staszewski Marek M Stasiak Anna A Karcz Tadeusz T McNaught Flores Daniel D Fogel Wiesława Agnieszka WA Kieć-Kononowicz Katarzyna K Leurs Rob R Walczyński Krzysztof K

MedChemComm 20190111 2

Previously, we have shown that 1-substituted-[4-(7-phenoxyheptylpiperazin-1-yl)butyl]guanidine with electron withdrawing substituents at position 4 in the benzyl moiety exhibits high in vitro affinities toward the guinea pig jejunal histamine H3 receptor with pA 2 ranging from 8.49 to 8.43. Here, we present data on the impact of replacement of the piperazine scaffold by the piperidine ring (compounds 2a and 2b), moving benzyl- and 4-trifluorometh ...[more]

PMID: 30881612

Similar Datasets

Project description:Histamine receptors (HRs) are excellent drug targets for the treatment of diseases, such as schizophrenia, psychosis, depression, migraine, allergies, asthma, ulcers, and hypertension. Among them, the human H(3) histamine receptor (hH(3)HR) antagonists have been proposed for specific therapeutic applications, including treatment of Alzheimer's disease, attention deficit hyperactivity disorder (ADHD), epilepsy, and obesity. However, many of these drug candidates cause undesired side effects through the cross-reactivity with other histamine receptor subtypes. In order to develop improved selectivity and activity for such treatments, it would be useful to have the three-dimensional structures for all four HRs. We report here the predicted structures of four HR subtypes (H(1), H(2), H(3), and H(4)) using the GEnSeMBLE (GPCR ensemble of structures in membrane bilayer environment) Monte Carlo protocol, sampling ∼35 million combinations of helix packings to predict the 10 most stable packings for each of the four subtypes. Then we used these 10 best protein structures with the DarwinDock Monte Carlo protocol to sample ∼50 000 × 10(20) poses to predict the optimum ligand-protein structures for various agonists and antagonists. We find that E206(5.46) contributes most in binding H(3) selective agonists (5, 6, 7) in agreement with experimental mutation studies. We also find that conserved E5.46/S5.43 in both of hH(3)HR and hH(4)HR are involved in H(3)/ H(4) subtype selectivity. In addition, we find that M378(6.55) in hH(3)HR provides additional hydrophobic interactions different from hH(4)HR (the corresponding amino acid of T323(6.55) in hH(4)HR) to provide additional subtype bias. From these studies, we developed a pharmacophore model based on our predictions for known hH(3)HR selective antagonists in clinical study [ABT-239 1, GSK-189,254 2, PF-3654746 3, and BF2.649 (tiprolisant) 4] that suggests critical selectivity directing elements are: the basic proton interacting with D114(3.32), the spacer, the aromatic ring substituted with the hydrophilic or lipophilic groups interacting with lipophilic pockets in transmembranes (TMs) 3-5-6 and the aliphatic ring located in TMs 2-3-7. These 3D structures for all four HRs should help guide the rational design of novel drugs for the subtype selective antagonists and agonists with reduced side effects.

Dataset Information

Design, synthesis, and in vitro and in vivo characterization of 1-{4-[4-(substituted)piperazin-1-yl]butyl}guanidines and their piperidine analogues as histamine H3 receptor antagonists.

Publications

Design, synthesis, and <i>in vitro</i> and <i>in vivo</i> characterization of 1-{4-[4-(substituted)piperazin-1-yl]butyl}guanidines and their piperidine analogues as histamine H<sub>3</sub> receptor antagonists.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure