N-Alkenyl and cycloalkyl carbamates as dual acting histamine H3 and H4 receptor ligands

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Abstract

Previous studies have shown that several imidazole derivatives posses affinity to histamine H3 and H4 receptors. Continuing our study on structural requirements responsible for affinity and selectivity for H3/H4 receptor subtypes, two series of 3-(1H-imidazol-4-yl)propyl carbamates were prepared: a series of unsaturated alkyl derivatives (19) and a series possessing a cycloalkyl group different distances to the carbamate moiety (1013). The compounds were tested for their affinities at the human histamine H3 receptor, stably expressed in CHO-K1 cells. Compounds 1, 2, 57, 1013 were investigated for their affinities at the human histamine H4 receptor co-expressed with Gαi2 and Gβ1γ2 subunits in Sf9 cells. To expand the pharmacological profile, compounds were further tested for their H3 receptor antagonist activity on guinea pig ileum and in vivo after oral administration to mice. All tested compounds exhibited good affinity for the human histamine H3 receptor with Ki values in the range from 14 to 194 nM. All compounds were active in vivo after peroral administration (p.o.) to Swiss mice, thus demonstrating their ability to cross the blood-brain barrier. The most potent H3 receptor ligand of these series was compound 5, 3-(1H-imidazol-4-yl)propyl pent-4-enylcarbamate with the highest affinity (Ki = 14 nM). Additionally, compound 3 showed remarkable central nervous system (CNS) H3R activity, increasing the Nτ-methylhistamine levels in mice with an ED50 value of 0.55 mg/kg, p.o. evidencing therefore, a twofold increase of inverse agonist/antagonist potency compared to the reference inverse agonist/antagonist thioperamide. In this study, the imidazole propyloxy carbamate moiety was kept constant. The different lipophilic moieties connected to the carbamate functionality in the eastern part of the molecule had a range of influences on the human H4 receptor affinity (154–1326 nM).

Graphical abstract

Two series of 3-(1H-imidazol-4-yl)propyl carbamates: a series of unsaturated alkyl derivatives and a series possessing a cycloalkyl group different distances to the carbamate moiety were prepared and tested for their affinities at human histamine H3 and H4 receptors. To expand pharmacological profile, compounds were also tested for their H3 receptor antagonist activity on guinea pig ileum and in vivo after oral administration to mice. Tested compounds exhibited good affinity for the hH3R and moderate to weak affinity for the hH4R.

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Introduction

Histamine has been found to exert tremendous influence over variety of physiological and pathophysiological processes. It mediates its effects through binding to four, so far known histamine receptor subtypes, designated H1 to H4 (H1R–H4R). All of them belong to the family of G-protein-coupled receptors, and are differentially expressed in various cell types. The H1R and H2R antagonists are for many years in clinical use, in the treatment of allergic conditions and gastric ulcers, respectively. The potential clinical applications for ligands of H3R and the H4R are being studied intensively. The H3R initially described in 1983 was found to be a constitutively active receptor mostly expressed in the brain.1, 2 H3Rs are identified as presynaptic autoreceptors, regulating the synthesis and the release of histamine, as well as heteroreceptors on non-histaminergic neurons controlling the release of many other important neurotransmitters, such as acetylcholine, norepinephrine, dopamine and serotonin.3 Given their localization and their ability to affect multiple neurotransmitter systems it is supposed that H3R antagonists/inverse agonists could be useful for the treatment of central nervous system (CNS) disorders such as Alzheimer’s disease, schizophrenia, attention-deficit and hyperactivity disorder (ADHD), narcolepsy, pain and obesity.4, 5, 6

The H4R is the latest identified receptor belonging to the histamine receptor family. The human H3R and H4R have about 31% sequence homology (54% in the transmembrane domains) and display similar genomic structures.7 In contrast to these structural similarities, the expression patterns of both receptors strongly differ. Whereas the H3R is predominantly localized in the brain, the H4R is expressed mainly in the peripheral tissues and cells of the immune system.7 Distinct expression patterns of H4R on various hematopoietic cells such as mast cells, basophils, eosinophils, T-cells and dendritic cells suggests it has an important role in the regulation of immune responses and inflammation.6, 8

Histamine H3R inverse agonists/antagonists belong to two general groups: imidazole containing compounds and non-imidazole derivatives.4, 9, 10, 11 Due to some structural similarities between human H3R and H4R, it is not surprising that numerous imidazole containing H3R ligands, that is, clobenpropit, imetit and thioperamide, have also significant affinity for the human H4R (Fig. 1). Many dual-acting H3R and H4R ligands have been successfully used as reference compounds and pharmacological tools in H3R and H4R research. It is supposed that such compounds with hybrid structures showing dual H3R and H4R antagonistic activity could possess therapeutic profile in the therapy of pain and cancer.6

While the current medicinal chemistry efforts are mainly focused on selective acting GPCRs ligands, and particularly on histamine H3 and H4 selective agonists/antagonists, there are also several efforts to develop dual acting H3/H4 compounds.12, 13, 14, 15, 16, 17, 18, 19 The identification of novel selective H4R ligands is still of interest to enlarge the knowledge of the pharmacological profile of the hH4R and distinct ligand-receptor interactions. Tritium-labeled N1-[3-(1H-imidazol-4-yl)propyl]-N2-propionylguanidine ([3H]UR-PI294), was discovered as a high-affinity histamine H3 and H4 receptor radioligand.12 Cyclopropane-based conformationally restricted analogs of 4-methylhistamine were designed and investigated as histamine H3/H4 receptor ligands. Pharmacological profiles of these analogs were shown to be different depending on the stereochemical character of the cyclopropane backbone and potent H3 and/or H4 receptor antagonists with low nanomolar Ki values were identified.13, 14 NG-Acylated imidazolyl-propylguanidines, originally described several years ago as H2R agonists15, 16, 17 were shown to display greater activity at H3R and H4Rs.18 Recently, Lim et al.19 has described a series of clobenpropit analogs as dual activity ligands for the histamine H3R and H4Rs. These compounds showed moderate to high affinity for both the human H3R and H4R but different intrinsic activity at the H4R from neutral antagonism to full agonism.19 General structures of dual acting H3/H4R ligands are shown in Fig 2.

In our studies, we focused on the synthesis and pharmacological evaluation of 3-(1H-imidazol-4-yl)propyl carbamates. This structural element had been intensively characterized as a potential H3R antagonist pharmacophore in different series of imidazole containing ligands.20, 21, 22, 23, 24 Recently, we reported about an expanded structure affinity/efficacy relationship (SAR) of branched alkyl carbamates of 3-(1H-imidazol-4-yl)propanol, that showed both high H3R antagonist activity and improved H4R affinity.25 To continue the investigation on dual H3/H4 receptor affinity and the structural requirements for affinity at the H3R and H4R, we introduced different substituents in the eastern part of the molecule. Slight structural variations on sterically restricted alkenyl and cycloalkyl residues caused subtle differences in ligand-receptor interactions that might influence the H3R and H4R potencies.

This paper describes the synthesis and pharmacological evaluations of two series of 3-(1H-imidazol-4-yl)propyl carbamates: a series of unsaturated alkyl derivatives (19) and a series possessing a cycloalkyl group at variable distances to the carbamate moiety (1013) (Table 1)

Section snippets

Chemistry

3-(1H-imidazol-4-yl)propanol was the key intermediate for all of the novel synthesized carbamates. It was prepared starting from urocanic acid in its trityl-protected and deprotected form as described by Stark et al.20 Carbamates 1, 46 and 913 were prepared by the method described earlier20, 21, 23 from appropriate amines by their reaction with excess of diphosgene, forming an intermediate isocyanate, which subsequently reacted with 3-(1H-imidazol-4-yl)propanol hydrochloride to furnish the

Pharmacological effects and discussion

All tested compounds exhibited histamine H3/H4 receptor affinity. Good to moderate affinity was observed for the hH3R with Ki values in the range from 14 to 194 nM and moderate to weak affinity for the hH4R (Ki values from 154 to 1326 nM). Among carbamates possessing an unsaturated moiety (19), the hH3R affinity depended mainly on the chain length and on the position of unsaturated double bond. The weakest affinity is exhibited by butenyl derivatives (1 and 2) and elongation of the chain length

Conclusions

As a continuation of the search for 3-(1H-imidazol-4-yl) propanol carbamates with dual histamine H3R/H4R affinity, unsaturated alkyl derivatives (19) and those possessing a cycloalkyl group in different distances to the carbamate moiety (1013) were synthesized. Tested compounds exhibited good affinity for the hH3R and moderate to weak affinity for the hH4R. These results indicate that restricted alkenyl analogs may provide greater selectivity for H3R over H4R. For example, the hex-3-enyl

Chemistry

Melting points were determined on a MEL-TEMP II apparatus and are uncorrected. 1H NMR spectra were recorded on a Varian-Mercury 300 MHz spectrometer or on a Bruker AC 300 (300 MHz) in DMSO-d6 or CDCl3. Chemical shifts are expressed in ppm downfield from internal tetramethylsilane as reference. Data are reported in the following order: multiplicity (br, broad; def, deformed; s, singlet; d, doublet; dq, doublet of quartets; t, triplet; m, multiplet; qu, quintet; q, quartet; sc, sextet; Cyhexl,

Acknowledgment

The authors acknowledge the partial support of ESF COST Action BM0806 ‘Recent advances in histamine receptor H4R research’, financed by EU-FP7, Grant No. 594/N-COST/2009/0 and that of LOEWE MFF.

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