Kamil Kuder

Synthesis and biological activity of tricyclic cycloalkylimidazo-, pyrimido- and diazepinopurinediones

Syntheses and physicochemical properties of N-cycloalkyl-substituted imidazo-, pyrimido- and 1,3-diazepino[2,1-f]purinediones are described. These derivatives were synthesized by cyclization of 7-halogenoalkyl-8-bromo-1,3-dimethylxanthine derivatives with aminocycloalkanes. The obtained compounds (1-33) were evaluated for their affinity to rat adenosine A(1) and A(2A) receptors. Selected compounds were additionally investigated for affinity to the human A(1), A(2A), A(2B) and A(3) receptor subtypes. The results of the radioligand binding assays at adenosine A(1) and A(2A) receptors showed that most of the compounds exhibited adenosine A(2A) receptor affinity at micromolar or submicromolar concentrations; an annelated pyrimidine ring was beneficial for A(2A) affinity. The most potent A(2A) ligands of the present series were compounds 6 (K(i) 0.33 μM rat A(2A), 0.31 μM human A(2A)), 8 (K(i) 0.98 μM rat A(2A), 0.42 μM human A(2A)) and 15 (K(i) 0.24 μM rat A(2A), 0.61 μM human A(2A)) with the latter one showing high A(2A) selectivity. In NaCl shift assay, 15 was shown to be an antagonist at A(2A) receptors. This result was confirmed for the best compounds 6, 8, 15 in cAMP accumulation studies. A 3D-QSAR equation with a good predicting power (q(2) = 0.88) for A(2A) AR affinity was obtained. The compounds were evaluated in vivo as anticonvulsants in MES and ScMet tests and examined for neurotoxicity in mice (i.p.). Most of them showed anticonvulsant activity in chemically induced seizures; among them the diazepinopurinediones were the best (e.g. 31) showing protection in both tests on short time symptoms, without signs of neurotoxicity. Five compounds, 8, 17, 20, 29, and 31, exhibited anticonvulsant activity after peroral application in rats. Structure-activity relationships are discussed including the analysis of lipophilic and spatial properties. The new compounds, which contain a basic nitrogen atom and can therefore be protonated, may be good starting points for obtaining A(2A) antagonists with good water-solubility.

Dual-Acting Diether Derivatives of Piperidine and Homopiperidine with Histamine H3 Receptor Antagonistic and Anticholinesterase Activity

The study presents novel biological properties of diether derivatives of homo‐ or substituted piperidine ligands of the histamine H3 receptor. The compounds were evaluated for their inhibitory potency against acetylcholinesterase (AChE) from the electric eel and butyrylcholinesterase (BuChE) from horse serum. The most interesting multifunctional compound 13 displayed high affinity for the cloned hH3R (Ki = 3.48 nM) and moderate inhibitory potency against both enzymes (IC50 AChE = 7.91 µM and BuChE = 4.97 µM). Molecular modeling studies revealed interactions with key amino acid residues in the homology model of histamine H3 receptor ligands, as well as the binding model for AChE and BuChE in the catalytic and peripheral active sites.

Non-imidazole-based histamine H3 receptor antagonists with anticonvulsant activity in different seizure models in male adult rats

A series of twelve novel non-imidazole-based ligands (3–14) was developed and evaluated for its in vitro binding properties at the human histamine H3 receptor (hH3R). The novel ligands were investigated for their in vivo protective effects in different seizure models in male adult rats. Among the H3R ligands (3–14) tested, ligand 14 showed significant and dose-dependent reduction in the duration of tonic hind limb extension in maximal electroshock (MES)-induced seizure model subsequent to acute systemic administration (5, 10, and 20 mg/kg, intraperitoneally), whereas ligands 4, 6, and 7 without appreciable protection in MES model were most promising in pentylenetetrazole (PTZ) model. Moreover, the protective effect observed for ligand 14 in MES model was lower than that observed for the reference drug phenytoin and was entirely abrogated when rats were co-administered with the brain-penetrant H1R antagonist pyrilamine (PYR) but not the brain-penetrant H2R antagonist zolantidine (ZOL), demonstrating that histaminergic neurotransmission by activation of postsynaptically located H1Rs seems to be involved in the protective action. On the contrary, PYR and ZOL failed to abrogate the full protection provided by 4 in PTZ model and the moderate protective effect by 14 in strychnine (STR) model. Moreover, the experimental and in silico estimation of properties such as metabolism was performed for five selected test compounds. Also, lipophilicity using planar reversed-phase thin-layer chromatography method was included for better understanding of the molecular properties of the tested compounds. Additionally, the absorption, distribution, metabolism, and elimination and toxicity parameters were evaluated for the most promising compounds 2, 4, 6, 7, and 14 utilizing in vitro methods. These interesting results highlight the potential of H3R ligands as new antiepileptic drugs or as adjuvants to available epilepsy medications.

Piperidine variations in search for non-imidazole histamine H3 receptor ligands

Synthesis and biological evaluation of the novel histamine H(3) receptor ligands is described. Two series of ethers (aliphatic and aromatic) have been prepared by four different methods. Compounds were evaluated for their affinities at recombinant human H(3) receptor stably expressed in CHO cells. The ethers show from low to moderate in vitro affinities in nanomolar concentration range. The most potent compound was the 1-[3-(4-tert-butylphenoxy)propyl]-4-piperidino-piperidine 16 (hH(3)R K(i)=100 nM). Several members of the new series investigated under in vivo conditions, proved to be inactive.

Chlorophenoxy aminoalkyl derivatives as histamine H(3)R ligands and antiseizure agents.

A series of twenty new chlorophenoxyalkylamine derivatives (9-28) was synthesized and evaluated on their binding properties at the human histamine H3 receptor (hH3R). The spacer alkyl chain contained five to seven carbon atoms. The highest affinities have shown the 4-chloro substituted derivatives 10 and 25 (Ki=133 and 128 nM, respectively) classified as antagonists in cAMP accumulation assay (EC50=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) ED50 values of 14 mg/kg and 13.18 mg/kg, respectively. Protective indexes (PI=TD50/ED50) were 3.2 for 20 and 3.8 for 26. Moreover, molecular modeling and docking studies were undertaken to explain affinity at hH3R 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.

Diether derivatives of homo- or substituted piperidines as non-imidazole histamine H3 receptor ligands

Synthesis and biological activities of a series of homo- or substituted piperidine unsymmetrical diethers are described. The novel compounds were evaluated for histamine H(3) receptor binding affinities at recombinant human H(3) receptor stably expressed in HEK-293 cells. All diethers showed in vitro affinities in nanomolar concentration range. The most potent compounds are 1-[3-(3-(4-chlorophenoxy)propoxy)propyl]-3-methylpiperidine 11 (K(i)=3.2 nM) and 1-[3-(3-(4-chlorophenoxy)propoxy)propyl]azepane 13 (K(i)=3.5 nM).

(2-Arylethenyl)-1,3,5-triazin-2-amines as a novel histamine H4 receptor ligands.

Within the constantly growing number of histamine H4 (H4R) 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 H4 receptors were evaluated in radioligand binding assays with use of Sf9 cells, transiently expressing human H4R. Pharmacological studies results allowed to identify 4-[(E)-2-(3-chlorophenyl)ethenyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (Ki = 253 nM) as the most potent compound in the present series.

Synthesis and biological activity of novel tert -butyl and tert -pentylphenoxyalkyl piperazine derivatives as histamine H 3 R ligands

As a continuation of our search for novel histamine H3 receptor ligands, a series of twenty four new tert-butyl and tert-pentyl phenoxyalkylamine derivatives (2-25) was synthesized. Compounds with three to four carbon atoms alkyl chain spacer were evaluated for their binding properties at human histamine H3 receptor (hH3R). The highest affinities were observed for 4-pyridyl derivatives 4, 10, 16 and 22 (Ki = 16.0-120 nM). As it has been shown in docking studies, those specific heteroaromatic 4-N piperazine substituents might interact with one of the key receptor interacting amino acids. Moreover, the most promising compounds exhibited anticonvulsant activity in the maximal electroshock-induced seizure (MES) model in mice. Furthermore, the blood-brain barrier penetration, the functional H3R antagonist potency as well as the pro-cognitive properties in the passive avoidance test were demonstrated for compound 10. In order to estimate drug-likeness of compound 10,in silico and experimental evaluation of metabolic stability in human liver microsomes was performed. In addition, paying attention to the results obtained within this study, the 4-pyridyl-piperazino moiety has been established as a new bioisosteric piperidine replacement in H3R ligands.

Histamine H3 receptor ligands in the group of (homo)piperazine derivatives

Since its discovery in 1983, followed by gene cloning in 1999, the histamine H3 receptor served as an outstanding target for drug discovery. The wide spectrum of possible therapeutic implications makes H3Rs one of the most researched areas in the vast GPCR ligands field - started from imidazole containing ligands, through various successful imidazole replacements, with recent introduction of Wakix® to pharmaceutical market. One such replacement is piperazine moiety, a significant versatile scaffold in rational drug design for most of the GPCR ligands. Therefore, herein, we review ligands built on piperazine, as well as its seven membered analogue azepine, that target H3Rs and their potential therapeutical applications, in order to elucidate the current state of the art in this vast field. Due to a high level of structural divergence among compounds described herein, we decided to divide them into groups, where the key division element was the position of nitrogen basicity decreasing moieties in (homo)piperazine ring. Paying attention to a number of published structures and their overall high biological activity, one can realize that the (homo)piperazine scaffold bids a versatile template also for histamine H3 receptor ligands. With two possible substitution sites and therefore a number of possible structural combinations, piperazine derivatives stand as one of the largest group of high importance among H3R ligands.

Monocyclic and Fused Azines and Azoles as Histamine H 4 Receptor Ligands.

The histamine H4 receptor has stood out since its discovery and identification in 2000 as an important target in the search for potential new drugs for the treatment of inflammatory and allergic diseases such as rhinitis, pruritus and asthma. Thus, in the last decade, both industry and academia have performed an intensive and productive search for new ligands of this newest subtype of histamine receptor. The most promising compounds found include monocyclic and fused azines, and azoles such as bispyrimidines, di- and triaminopyrimidines, quinazolines, imidazoles, indoles, benzimidazoles and benzazoles. The aim of this review is to give an insight into the current state of the art in the field of histamine H4 receptor research, focusing mainly on the last five years.