Search

Introduction Presently available PET ligands for the NMDAr ion channel generally suffer from fast metabolism. The purpose of this study was to develop a metabolically more stable ligand for the NMDAr ion channel, taking [11C]GMOM ([11C]1) as the lead compound. Methods [11C]1, its fluoralkyl analogue [18F]PK209 ([18F]2) and the newly synthesized fluorovinyloxy analogue [11C]7b were evaluated ex vivo in male Wistar rats for metabolic stability. In addition, [11C]7b was subjected to a biodistribution study and its affinity (Ki) and lipophilicity (logD7.4) values were determined. Results The addition of a vinyl chain in the fluoromethoxy moiety did not negatively alter the affinity of [11C]7b for the NMDAr, while lipophilicity was increased. Biodistribution studies showed higher uptake of [11C]7b in forebrain regions compared with cerebellum. Pre-treatment with MK-801 decreased the overall brain uptake significantly, but not in a region-specific manner. 45 min after injection 78, 90 and 87% of activity in the brain was due to parent compound for [11C]1, [18F]2 and [11C]7b, respectively. In plasma, 26–31% of activity was due to parent compound. Conclusion Complete substitution of the alpha-carbon increased lipophilicity to more favorable values. Substitution of one or more hydrogens of the alpha-carbon atom in the methoxy moiety improved metabolic stability. In plasma, more parent compound was found for [18F]2 and [11C]7b then for [11C]1, although differences were not significant. At 45 min, significantly more parent [18F]2 and [11C]7b was measured in the brain compared with [11C]1.

The N-Methyl-d-Aspartate receptor (NMDAR) is involved in many neurological and psychiatric disorders including Alzheimer's disease and schizophrenia. The aim of this study was to develop a positron emission tomography (PET) ligand to assess the bio-availability of the NMDAR ion channel in vivo. A series of tri-N-substituted diarylguanidines was synthesized and their in vitro binding affinities for the NMDAR ion channel assessed in rat forebrain membrane fractions. Compounds 21, 23 and 26 were radiolabeled with either carbon-11 or fluorine-18 and ex vivo biodistribution and metabolite studies were performed in Wistar rats. Biodistribution studies showed high uptake especially in prefrontal cortex and lowest uptake in cerebellum. Pre-treatment with MK-801, however, did not decrease uptake of the radiolabeled ligands. In addition, all three ligands showed fast metabolism.

Labeled with carbon‐11, N‐(2‐chloro‐5‐thiomethylphenyl)‐N′‐(3‐methoxyphenyl)‐N′‐methylguanidine ([11C]GMOM) is currently the only positron emission tomography (PET) tracer that has shown selectivity for the ion‐channel site of N‐methyl‐D‐aspartate (NMDA) receptors in human imaging studies. The present study reports on the selectivity profile and in vitro binding properties of GMOM. The compound was screened on a panel of 80 targets, and labeled with tritium ([3H]GMOM). The binding properties of [3H]GMOM were compared to those of the reference ion‐channel ligand [3H](+)‐dizocilpine maleate ([3H]MK‐801), in a set of concentration‐response, homologous and heterologous inhibition, and association kinetics assays, performed with repeatedly washed rat forebrain preparations. GMOM was at least 70‐fold more selective for NMDA receptors compared to all other targets examined. In homologous inhibition and concentration‐response assays, the binding of [3H]GMOM was regulated by NMDA receptor agonists, albeit in a less prominent manner compared to [3H]MK‐801. Scatchard transformation of homologous inhibition data produced concave upward curves for [3H]GMOM and [3H]MK‐801. The radioligands showed bi‐exponential association kinetics in the presence of 100 μmol L−1 l‐glutamate/30 μmol L−1 glycine. [3H]GMOM (3 nmol L−1 and 10 nmol L−1) was inhibited with dual affinity by (+)‐MK‐801, (R,S)‐ketamine and memantine, in both presence and absence of agonists. [3H]MK‐801 (2 nmol L−1) was inhibited in a monophasic manner by GMOM under baseline and combined agonist conditions, with an IC50 value of ~19 nmol L−1. The non‐linear Scatchard plots, biphasic inhibition by open channel blockers, and bi‐exponential kinetics of [3H]GMOM indicate a complex mechanism of interaction with the NMDA receptor ionophore. The implications for quantifying the PET signal of [11C]GMOM are discussed.

There are currently no positron emission tomography (PET) radiotracers for the GluN2B (NR2B) binding sites of brain N-methyl-D-aspartate (NMDA) receptors. In rats, the GluN2B antagonist Ro25-6981 reduced the binding of N-((5-(4-fluoro-2-[Eight 90-min dynamic [[The present results show that [

The N-methyl-d-aspartate receptor (NMDAr) is involved in many neurological and psychiatric disorders including Alzheimer's disease and schizophrenia. Currently, it is not possible to assess NMDAr availability in vivo. The purpose of this study was to develop a positron emission tomography (PET) ligand for the NMDAr ion channel. A series of di- and tri-N-substituted diarylguanidines was synthesized. In addition, in vitro binding affinity for the NMDAr ion channel in rat forebrain membrane fractions was assessed. Compounds 10, 11 and 32 were radiolabeled with either carbon-11 or fluorine-18. Ligands [(11)C]10 and [(18)F]32 were evaluated ex vivo in B6C3 mice. Biodistribution studies showed higher uptake of [(11)C]10 and [(18)F]32 in forebrain regions compared with cerebellum. In addition, for [(11)C]10 54% and for [(18)F]32 70% of activity in the brain at 60min was due to intact tracer. Pre-treatment with MK-801 (0.6mg·kg(-1), ip) slightly decreased uptake in NMDAr-specific regions for [(18)F]32, but not for [(11)C]10. As such [(18)F]32 has the best characteristics as a PET tracer for the ion channel of the NMDAr.

Presently available PET ligands for the NMDAr ion channel generally suffer from fast metabolism. The purpose of this study was to develop a metabolically more stable ligand for the NMDAr ion channel, taking [[The addition of a vinyl chain in the fluoromethoxy moiety did not negatively alter the affinity of [Complete substitution of the alpha-carbon increased lipophilicity to more favorable values. Substitution of one or more hydrogens of the alpha-carbon atom in the methoxy moiety improved metabolic stability. In plasma, more parent compound was found for [

Introduction The N-methyl-D-Aspartate (NMDA) receptor plays an important role in learning and memory. Overactivation is thought to play an important role in neurodegenerative disorders such as Alzheimer's disease. Currently, it is not possible to assess N-methyl-D-aspartate receptor (NMDAr) bio-availability in vivo. The purpose of this study was to develop a positron emission tomography (PET) ligand for the NR2B binding site of the NMDA receptor. Methods N-((5-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamine was radiolabelled with carbon-11 in the phenyl moiety. Biodistribution and blocking studies were carried out in anaesthetized mice and in non-anaesthetized rats. Results N-((5-(4-fluoro-2-[ 11 C]methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamine was prepared in 49±3% (decay-corrected) yield, affording 4.1±0.3GBq of formulated product at the end of synthesis with a radiochemical purity of >99% and with a specific activity of 78±10GBq/μmol. Conclusion A new NR2B PET ligand was developed in high yield. [ 11 C]4 readily enters the brain and binds to the NR2B subunit-containing NMDAr in the rodent brain. High sigma-1 receptor binding may, however, limit its future application as a PET probe for imaging the NR2B subunit-containing NMDAr. Anaesthesia has an effect on NMDAr function and therefore can complicate interpretation of preclinical in vivo results. In addition, effects of endogenous compounds cannot be excluded. Despite these potential limitations, further studies are warranted to investigate the values of [ 11 C]4 as an NR2B PET ligand.

Labeled with carbon-11, N-(2-chloro-5-thiomethylphenyl)-N'-(3-methoxyphenyl)-N'-methylguanidine ([11 C]GMOM) is currently the only positron emission tomography (PET) tracer that has shown selectivity for the ion-channel site of N-methyl-D-aspartate (NMDA) receptors in human imaging studies. The present study reports on the selectivity profile and in vitro binding properties of GMOM. The compound was screened on a panel of 80 targets, and labeled with tritium ([3 H]GMOM). The binding properties of [3 H]GMOM were compared to those of the reference ion-channel ligand [3 H](+)-dizocilpine maleate ([3 H]MK-801), in a set of concentration-response, homologous and heterologous inhibition, and association kinetics assays, performed with repeatedly washed rat forebrain preparations. GMOM was at least 70-fold more selective for NMDA receptors compared to all other targets examined. In homologous inhibition and concentration-response assays, the binding of [3 H]GMOM was regulated by NMDA receptor agonists, albeit in a less prominent manner compared to [3 H]MK-801. Scatchard transformation of homologous inhibition data produced concave upward curves for [3 H]GMOM and [3 H]MK-801. The radioligands showed bi-exponential association kinetics in the presence of 100 μmol L-1 l-glutamate/30 μmol L-1 glycine. [3 H]GMOM (3 nmol L-1 and 10 nmol L-1 ) was inhibited with dual affinity by (+)-MK-801, (R,S)-ketamine and memantine, in both presence and absence of agonists. [3 H]MK-801 (2 nmol L-1 ) was inhibited in a monophasic manner by GMOM under baseline and combined agonist conditions, with an IC50 value of ~19 nmol L-1 . The non-linear Scatchard plots, biphasic inhibition by open channel blockers, and bi-exponential kinetics of [3 H]GMOM indicate a complex mechanism of interaction with the NMDA receptor ionophore. The implications for quantifying the PET signal of [11 C]GMOM are discussed.

In order to replace the P2–P1 amide group, different 1-cycloalkenyls and 2-aryls were studied in the place of the P1 pyrrolidine group of a 4-phenylbutanoyl- l -Pro-pyrrolidine structure, which is a well-known prolyl oligopeptidase inhibitor SUAM-1221. The 1-cyclopentenyl and the 2-thienyl groups gave novel compounds, which were equipotent with the corresponding pyrrolidine-analog SUAM-1221. It was shown that the P2–P1 amide group of POP inhibitors can be replaced by an α,β-unsaturated carbonyl group or the aryl conjugated carbonyl group.

Introduction: The present study was designed to assess whether [18F]PK-209 (3-(2-chloro-5-(methylthio)phenyl)-1-(3-([18F]fluoromethoxy)phenyl)-1-methylguanidine) is a suitable ligand for imaging the ion-channel site of N-methyl-D-aspartate receptors (NMDArs) using positron emission tomography (PET). Methods: Dynamic PET scans were acquired from male rhesus monkeys over 120min, at baseline and after the acute administration of dizocilpine (MK-801, 0.3mg/kg; n=3/condition). Continuous and discrete arterial blood samples were manually obtained, to generate metabolite-corrected input functions. Parametric volume-of-distribution (VT) images were obtained using Logan analysis. The selectivity profile of PK-209 was assessed in vitro, on a broad screen of 79 targets. Results: PK-209 was at least 50-fold more selective for NMDArs over all other targets examined. At baseline, prolonged retention of radioactivity was observed in NMDAr-rich cortical regions relative to the cerebellum. Pretreatment with MK-801 reduced the VTof [18F]PK-209 compared with baseline in two of three subjects. The rate of radioligand metabolism was high, both at baseline and after MK-801 administration. Conclusions: PK-209 targets the intrachannel site with high selectivity. Imaging of the NMDAr is feasible with [18F]PK-209, despite its fast metabolism. Further in vivo evaluation in humans is warranted.

A series of ionizable prolyl oligopeptidase inhibitors were developed through the introduction of a pyridyl group to the P3 position of the prolyl oligopeptidase inhibitor structure. The study was performed on previously developed prolyl oligopeptidase inhibitors with proline mimetics at the P2 position. The 3-pyridyl group resulted in equipotent compounds as compared to the parent compounds. It was shown that the pyridyl group improves water solubility and, in combination with a 5(R)-tert-butyl-l-prolyl group at the P2 position, good lipophilicity can be achieved.

Prolyl oligopeptidase (POP) is a serine protease that specifically hydrolyses small peptides at the carboxyl end of the proline residue. POP has gained pharmaceutical interest, since its inhibitors have been shown to have antiamnesic properties in rat. We examined the effect of the 2( S )-substituents CN and COCH 2 OH at the P1 site of the parent inhibitors isophthalic acid 2( S )-(cyclopentanecarbonyl)pyrrolidine- l -prolyl-pyrrolidine amide and 4-phenylbutanoyl- l -prolyl-pyrrolidine and bulky 5- t -butyl group at the P2 site l -prolyl residue of the parent inhibitor 4-phenylbutanoyl- l -prolyl-pyrrolidine on the binding kinetics to the enzyme. In addition, we studied the duration of POP inhibition in the rat tissues in vivo after i.p. administration. CN and COCH 2 OH substituents at the P1 site pyrrolidine group were found to greatly increase the affinity of the inhibitor and the enzyme–inhibitor complex half-life. In addition, 5- t -butyl group at the P2 site l -prolyl residue increased the dissociation half-life of the enzyme–inhibitor complex, without much affecting the inhibitory potency. The duration of the inhibition in the rat tissues followed the inhibition kinetic properties in that the compounds with fast dissociation produced shorter inhibition in the rat tissues than the compounds with slow dissociation. The duration of POP inhibition of compounds was evidently not governed by their serum clearance. The fact that the in vivo pharmacodynamic behaviour of POP inhibitors can be predicted by their in vitro-properties may be of importance when designing therapeutically useful POP inhibitors.

A series of dicarboxylic acid azacycle l-prolyl-pyrrolidine amides was synthesized, and their inhibitory activity against prolyl oligopeptidase (POP) from porcine brain was tested. Three different azacycles were tested at the position beyond P3 and six different dicarboxylic acids at the P3 position. l-Prolyl-pyrrolidine and l-prolyl-2(S)-cyanopyrrolidine were used at the P2-P1 positions. The IC(50) values ranged from 0.39 to 19000 nM. The most potent inhibitor was the 3,3-dimethylglutaric acid azepane l-prolyl-2(S)-cyanopyrrolidine amide. Molecular docking (GOLD) was used to analyze binding interactions between different POP inhibitors of this type and the POP enzyme. The data set consisted of the novel inhibitors, inhibitors published previously by our group, and well-known reference compounds. The alignments were further analyzed using comparative molecular similarity indices analysis. The binding of the inhibitors was consistent at the P1-P3 positions. Beyond the P3 position, two different binding modes were found, one that favors lipophilic structures and one that favors nonhydrophobic structures.

POP (prolyl oligopeptidase) specifically hydrolyses a number of small proline-containing peptides at the carboxy end of the proline residue and POP inhibitors have been shown to have cognition-enhancing properties. It has been noted that certain functional groups at the P1 site of the inhibitor, which correspond to the substrate residue on the N-terminal side of the bond to be cleaved, increase the inhibitory potency. However, detailed mechanistic and kinetic analysis of the inhibition has not been studied. In the present study, we examined the effect of different functional groups at the P1 site of the parent inhibitor isophthalic acid bis-(L-prolylpyrrolidine) amide on the binding kinetics to POP. Addition of CHO, CN or COCH(2)OH groups to the P1 site increased the inhibitory potency by two orders of magnitude (K(i)=11.8-0.1 nM) and caused a clear slow-binding inhibition. The inhibitor containing a CHO group had the lowest association rate constant, k(on)=(2.43+/-0.12) x 10(5) M(-1) x s(-1), whereas the inhibitor with a CN group exhibited the fastest binding, k(on)=(12.0+/-0.08)x10(5) M(-1) x s(-1). In addition, the dissociation rate was found to be crucially dependent on the type of the functional group. Compounds with COCH(2)OH and CHO groups had much longer half-lives of dissociation (over 5 h) compared with the compound with the CN group (25 min), although the K(i) values of the compounds were relatively similar. A possibility to optimize the duration of inhibition by changing the functional group at the P1 site is important when planning therapeutically useful POP inhibitors.

Isophthalic acid bis(l-prolyl-pyrrolidine) amide is a very potent prolyl oligopeptidase inhibitor, but it has a log P value of -0.2, which is very low for a compound targeted to the brain. Therefore, these types of compounds were further modified to improve the structure-activity relationships, with the focus on increasing the log P value. The inhibitory activity against prolyl oligopeptidase from pig brain was tested in vitro. The most promising compounds resulted from replacing the pyrrolidinyl group at the P5 site by cycloalkyl groups, such as cyclopentyl and cyclohexyl groups, and by a phenyl group. These compounds are slightly more potent, and they have a significantly higher log P value. The potency of these compounds was further increased by replacing the pyrrolidinyl group at the P1 site by 2(S)-cyanopyrrolidinyl and 2(S)-(hydroxyacetyl)pyrrolidinyl groups.

In the N-acyl- l -prolyl-pyrrolidine type of prolyl oligopeptidase inhibitors the l -prolyl group was replaced by different 5-alkyl- l -prolyl groups, resulting in a series of N-acyl-5-alkyl- l -prolyl-pyrrolidines. Since N-amides of 5-alkyl- l -prolines are conformationally more rigid than those of l -proline, the main objective was to make more rigid prolyl oligopeptidase inhibitors. In the series of compounds where the N-acyl group was a Boc group, the 5(R)-tert-butyl group increased the potency strongly. A similar effect was not observed for the 5(S)-tert-butyl group. In the series of compounds where the N-acyl group was a 4-phenylbutanoyl group, the 5(R)-tert-butyl, 5(R)-methyl and 5(S)-methyl groups did not have an effect on the potency [the 5(S)-tert-butyl group was not tested in this series]. As an additional effect, the 5-tert-butyl groups increased the log P of the compounds 1.5 log units, which might be beneficial when targeting the compounds to the brain.

New dicarboxylic acid bis(L-prolyl-pyrrolidine) amides were synthesized, and their inhibitory activity against prolyl oligopeptidase from pig brain was tested in vitro. As compared with earlier described prolyl oligopeptidase inhibitors, these new compounds have in common an L-prolyl-pyrrolidine moiety, but the typical lipophilic acyl end group is replaced by another L-prolyl-pyrrolidine moiety connected symmetrically with a short dicarboxylic acid linker. These compounds are a new type of peptidomimetic prolyl oligopeptidase inhibitor.

New 4-phenylbutanoyl-2( S )-acylpyrrolidines and 4-phenylbutanoyl- l- prolyl-2( S )-acylpyrrolidines were synthesized. Their inhibitory activity against prolyl oligopeptidase from pig brain was tested in vitro. In the series of 4-phenylbutanoyl-2( S )-acylpyrrolidines, the cyclopentanecarbonyl and benzoyl derivatives were the best inhibitors having IC 50 values of 30 and 23 nM, respectively. This series of compounds shows that the P1 pyrrolidine ring, which is common in most POP inhibitors, can be replaced by either a cyclopentyl ring or a phenyl ring, causing only a slight decrease in the inhibitory activity. In the series of 4-phenylbutanoyl- l -prolyl-2( S )-acylpyrrolidines the cyclopentanecarbonyl and benzoyl derivatives were not as active as in the series of 4-phenylbutanoyl-2( S )-acylpyrrolidines. The hydroxyacetyl derivative did however show high inhibitory activity. This compound is structurally similar to JTP-4819, which is one of the most potent prolyl oligopeptidase inhibitors. The acyl group in the two series of new compounds seems to bind to different sites of the enzyme, since the second series of new compounds did not show the same cyclopentanecarbonyl or benzoyl specificity as the first series.

This study proposes a new mechanism of activation of the histamine H3-receptor based on stabilization of the active state of the receptor protein by a proton relay process. A series of histamine H3-receptor agonists and one antagonist, all containing an imidazole and a side chain amino group, were studied using 1H NMR and ab initio quantum mechanical calculations. A significant correlation (r = −0.87) between the formation energy of the active reaction intermediate and the agonistic activity is found. The calculated proton-transfer energies and pKa values of the reaction intermediates (at the MP2/6-31+G*//HF/6-31+G* level in the gas and aqueous phases), as well as, 1H NMR conformational analysis, enable a qualitative and quantitative determination of intramolecular hydrogen bonding and its effect on proton release from the imidazole N(τ)-atom. The results indicate that the histamine H3-receptor is not activated by a proton release from imidazole N(τ)-atom but through adoption of a folded conformation of t...

Conformational stabilization by intramolecular hydrogen bonding of two histamine H 3 -receptor agonists is studied by 1 H NMR. Stabilization of each individual conformation of the compounds by intramolecular hydrogen bonding is not strong at physiological pH and temperature. However, 52% – 61% of the molecules exist in conformations where an intramolecular hydrogen bond is possible.

With the aim to replace the natural amino acid proline by a proline mimetic structure, a cyclopent-2-enecarbonyl moiety was studied at the P2 position of prolyl oligopeptidase (POP) inhibitors. The cyclopent-2-enecarbonyl moiety proved to be an excellent proline mimetic at the P2 position of POP inhibitors. The replacement is particularly useful when increased lipophilicity is needed.

Summary The synthesis and in vitro pharmacology of some dimaprit analogues with histamine H 2 -agonistic and additional histamine H 1 -antagonistic activities are discussed. 2-Amino-5-(2-aminoethyl)thiazoles can be considered chemically as ring-closed dimaprit analogues, and so the alkylisothiourea structural moiety of dimaprit, S -[3-( N,N -dimethylamino)propyl]isothiourea, could replace the propylthiazole or propylimidazole structural moieties of impromidine-like histamine H 2 -agonists. The H 2 -agonistic activities of a number of N -(3,3-diphenylpropyl)- N′ -(ω-isothioureidoalkyl)guanidines indicate that 2-amino-5-(2-aminoethyl)thiazole can indeed be considered as a ring-closed dimaprit analogue.

The synthesis and in vitro pharmacology of a series of new cardiovascular hybrid molecules, which could be useful for the treatment of certain types of hypertension and at the same time for the treatment of cardiac ischemic disease, are discussed. Two types of 1,4-dihydropyridine Ca2+-channel blockers have been studied. In general, hybrid molecules possessing a diethyl 2-(ω-aminoalkylthio)methyl-2,6-dimethyl-4-[(substituted)phenyl]-1,4-dihydropyridine-3,5-dicarboxylic structural moiety and a histamine H2-agonistic structural moiety are more potent L-type calcium-channel blockers and histamine H2-agonists than hybrid molecules containing a diethyl 4-[2-(ω-aminoalkoxy)phenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic structural moiety.

To investigate stereospecificity and the mechanism of activation of the histamine H3-receptor, a series of 2-(R and S)-amino-3-(1H-imidazol-4(5)-yl)propyl ether derivatives were synthesized. In these compounds, the structures of the well-known antagonist iodoproxyfan and the full agonists R- or S-(alpha)-methylhistamine were combined in one molecule. The obtained "hybrid" molecules were tested for H3-receptor affinity on rat cerebral cortex. Some selected compounds were further screened for H3-receptor functional activity with GTPgamma[35S] autoradiography studies using rat brain tissue sections. The affinity of all the synthesized compounds (-log Ki = 5.9-7.9) was lower than that found for iodoproxyfan or two of its analogues; however, the compounds showed stereospecificity. The S-configuration of the series of 2-amino-3-(1H-imidazol-4(5)-yl)propyl ether derivatives, which resembles the stereochemistry of R-(alpha)-methylhistamine, was more favorable. Incorporation of an amino group in the propyl chain of iodoproxyfan and analogues did not alter the antagonistic behavior for compounds with an aromatic side chain. However, when also the aromatic moiety was replaced by a cyclohexyl group, the compounds behaved as agonists. This indicates that an interaction between the side chain amino group and the H3-receptor protein is involved in H3-receptor activation. The 2-(S)-amino-3-(1H-imidazol-4(5)-yl)propyl cyclohexylmethyl ether (23) has H3-receptor agonistic properties with high affinity for the histamine H3-receptor (-log Ki = 7.9 +/- 0.2) and might serve as a useful tool for further studies concerning drug design and receptor-ligand interactions.

The synthesis of (2S,5S)-Boc-5-tert-butylproline ethyl ester via the addition of tert-butylcuprate to (2S)-N-Boc-Δ5-dehydroproline ethyl ester, formed from (2S)-N-Boc-5-methoxyproline ethyl ester, gives an excellent yield of 94% and a high diastereoselectivity (2S,5S):(2S,5R) 78:22. This synthesis opens up a new synthetic route to (2S,5S)-5-tert-butylproline, which is a useful, conformationally rigid, analogue of l-proline.

(Cyclohexylmethyloxymethyl)(1H-imidazol-4-iomethyl)-(S)-ammonium dichloride, C(13)H(25)N(3)O(+).2Cl(-), and (4-bromobenzyl)(1H-imidazol-4-iomethyl)-(S)-ammonium dichloride, C(13)H(18)BrN(3)O(+).2Cl(-), are model compounds with different biological activities for evaluation of the histamine H3-receptor activation mechanism. Both title compounds occur in almost similar extended conformations.