Frontiers | Multiple Targeting Approaches on Histamine H3 Receptor Antagonists | Neuroscience
On the structure-activity relationship of histamine H2-receptor antagonists based to both single crystal X-ray structural and 1H-NMR analyses. Binding mode analysis and enrichment studies on homology models of the human of a histamine H3 receptor model through structure-activity relationships for. structure-activity relationship and physicochemical properties of H1- antihistamimnes  used for the binding mode analysis of different H1- antihistamines .
We were able to identify molecular features that are positively or negatively correlated with the ability of ligands to induce biased hH4R signalling. The current study is one of the first to use computational analysis Sirci et al.
Moreover, with a hH4R homology model, we could identify receptor regions important for biased hH4R signalling. This is a promising first step towards the identification of ligand efficacy hotspots that may allow the rational design of ligands with specific GPCR biased activity and that will aid the understanding of GPCR activation.
Forskolin and histamine were bought from Sigma-Aldrich St.
Synthesis of the indolecarboxamide analogues was previously described Engelhardt et al. Two million cells were seeded per 10 cm dish 1 day prior to transfection. Data analysis and statistical procedures All data were analysed with GraphPad Prism v5 software.
- A structure-activity relationship study of compounds with antihistamine activity.
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- Structure–activity relationship
Functional concentration—response curves were fitted to a three-parameter response model. Protonated forms for each molecule at pH 7. Stereoisomeric forms were considered for chiral compounds 44, 53, 65 and Molecular interaction fields MIFs were derived from interaction energies with the ligands at specific grid points, as determined by the H shapeDRY hydrophobicN1 H-bond acceptor and O H-bond donor probes defined in the GRID force field Goodford, with a grid spatial resolution of 0.
Partial least square analysis was used to correlate the MIFs with the intrinsic activities of the different indolecarboxamides. One latent variable LV1 was set up for the QSAR study as additional components did not lead to either fitting R2 or predictivity Q2 improvement data not shown. We used the pose of compound 1 as initial binding mode for the other ligands, which were rebuilt using MOE version The models were then subjected to energy minimization using the MMFF94x force field with fixed position of the protein backbone atoms.
Results Evaluation of indolecarboxamides in a cAMP reporter gene assay Forty-eight indolecarboxamides i. All other compounds including 1 JNJ Eff. Neuroleptics used for the treatment of schizophrenia usually inhibit dopamine D2-like receptors and other aminergic receptors, such as serotonin 5-HT2A receptor, dopamine D1 receptor D1R receptors, and other serotonin receptor subtypes Remington, The most important side effects of these neuroleptics are extrapyramidal side effects and weight gain problems Vuyyuru et al.
These side effects are related to their antagonistic properties at the dopamine D2-like and H1R, respectively Kroeze et al. Additionally, schizophrenic patients usually showed a significantly high level of N-methylhistamine in cerebral cerebrospinal fluid Ligneau et al. For this approach 4- 3-piperidinopropoxy phenyl was linked to several known neuroleptics. Resulting compounds showed high H3R affinity with Ki values between 4.
Compound 11 Figure 5 with a good overall profile and high H3R affinity was synthesized by merging 4- 3-piperidinopropoxy phenyl fragment with amitriptyline 12 Figure 5. This compound was selected for an early in vivo screening for central H3R antagonist potency on male Swiss mice. To determine the in vivo potency, an increase in N-methylhistamine level in the brain 90 min after the oral application of the compound was measured Von Coburg et al.
Using pharmacophore-based virtual screening, Lepailleur et al. Combined with the beneficial effects of H3R on neurodegenerative diseases, dual targeting of H3R and 5-HT4R would therapeutically be useful. One of the identified hits, compound 13 Figure 6 showed high affinities with Ki values of Scopolamine is a nonselective muscarinic antagonist, which partially blocks the cholinergic neurotransmission and is used to examine the cognitive enhancing effects of potential compounds Snyder et al.
Recently, different combinations between melatonin and another neuroprotection agent, e. Different H3R antagonists also showed neuroprotective actions Brioni et al. Therefore, the synthesis of ligands able to bind at both H3R and melatonin receptors could be useful for the treatment of the diseases mentioned above.
Melatonin is a methoxyindole-derived hormone secreted mainly by the pineal gland. The activation of MT1R and MT2R is not only important for the regulation of cardiac rhythms, but also for having antioxidant and neuroprotective effects Srinivasan et al. One good dual acting ligand was obtained by elongating the alkyl chain between the imidazole ring and the melatonin moiety with a pentyl linker. The elongation of the spacer can store the imidazole in a more peripheral region of the melatonin receptors.
In that region, negative interactions with positively charged amino groups are weakened. Therefore, compounds 14, 15; Figure 7 able to bind to both melatonin and histamine H3R with affinity in the micromolar concentration range were designed. The optimization of these ligands can be the next step for discovering new multiple targeting compounds that belong to the new melatonin-histamine combination. However, the efficacy of these drugs is noticeable only after weeks of treatment and do not improve cognitive functions of depressive patients, which prompt many physicians to co-prescribe stimulants with SSRI to provide subjective relief.
H3R antagonists produce wakefulness in animals without releasing dopamine or producing behavioral activation.
Such activation has been avoided due to the risk of allowing patients to act on their suicidal ideation Menza et al. Their effort was started with the identification of lead compounds with desirable SERT affinity, which could then be used as a template to introduce H3R antagonist activity. Two SSRI templates were designated, the first based on fluoxetine, which is the third most prescribed antidepressant drug 16, Figure 8 ; Wong et al.
Starting from fluoxetine template, the tertiary benzyl amines of 18—21 were replaced with the fluoxetine template, so that the known SSRI would serve as both, the lipophilic core and one of the basic amines. Several H3 amine side moieties were initially 3- or 4-substituted on both phenylene rings of fluoxetine rings A and B.
All the regioisomers had high affinity for the hH3R, but the 3-piperidinyl-propyloxy derivative provided the highest affinity for both the rat serotonin transporter rSERT and human serotonin transporter hSERT e. The same approach was applied for designing of hexahydropyrroloisoquinolines-derived dual H3R antagonists and SERT inhibitors. Nevertheless, unlike the fluoxetine scaffold, most simple substitutions on the aryl ring A of the hexahydropyrroloisoquinoline scaffold provided similar rSERT and hSERT affinity Keith et al.
Two high affinity compounds, the 4-methoxy derivative and the 3-pyridyl derivatives demonstrated good in vivo activities in serotonin potentiated head twitch model for SERT inhibition and blockade of imetit-induced drinking model for the H3R inhibition. In addition, these structures still retained affinity for the dopamine transporter DAT; Keith et al. Consequently, simpler templates from hexahydropyrroloisoquinoline were attempted, initially, by removal of the fused pyrrolidine ring and one chiral center to obtain the tetrahydroisoquinolines Letavic et al.
Structural optimization of tetrahydroisoquinolines derivatives was conducted using a large number of amines in order to improve the binding affinity at H3R, varying the physical properties of the resulting compounds and maintaining SERT affinity Keith et al.
Several modifications were attempted on the pendant piperidine ring; morpholine and substituted piperidines usually resulted in high affinity compounds.
Replacing the piperidine with piperazine afforded compounds that have variable affinity for the hH3R, depending greatly on the basicity of the terminal nitrogen. For example, small alkyl substituents on the piperazine provided compounds with high affinity for the H3R, but decreasing the basicity of the terminal nitrogen by addition of bulky groups lowered the affinity for the H3R.
Among the large number of derivatives that were synthesized, compound 24 Figure 8which was afforded by removal of the pyrrolidine ring of 23 together with the replacement of the piperidine ring with a morpholine, has improved rat pharmacokinetics and improved pharmacodynamics with a head twitch response Keith et al. Further simplification was conducted by removing one carbon on the tetrahydroisoquinoline, which deleted the last remaining stereocenter to provide the benzyl amine derivatives e.
The benzylic carbon of tetrahydroisoquinolines was replaced with an oxygen in order to improve overall physical properties Letavic et al. The 3-piperidinyl-propyloxy derivatives were not used in this series; instead, they used the alkyne and amide side chains corresponding to the known H3R antagonists 19 and The later modification was important to avoid any potential metabolic problems associated with 1,4-hydroxyquinone.
The benzamides benzyl amine derivatives were very potent with good selectivity over the norepinephrine transporter NET and DAT. One of the compounds, 26 Figure 8was extensively profiled in vivo and was found to have good rat pharmacokinetic and pharmacodynamics properties Table 1 ; Ly et al. Although not yet tested on humans, inhibition of the H3R makes it an attractive combination with SERT blockade in order to create a novel antidepressant treatment.
The inhibition of NE uptake is essential for the pain efficacy Leventhal et al. Using these results Altenbach et al. An H3R pharmacophore was linked to duloxetine analogs, cf. Ligands with dual inhibitory activities on both H3R and HMT could increase intersynaptic histamine levels in the CNS and may lead to beneficial procognitive effects in psychiatric and neurodegenerative diseases Apelt et al.
Even if they have low or missing in vivo activity, such ligands could greatly enhance histaminergic neurotransmission via inhibition of histamine H3 auto-receptors and reduce the catabolic rate for histamine degradation via HMT inhibition Grassmann et al. Most of the HMT inhibitors have a 4-aminoquinoline moiety in common e.
Variation of the spacer structure provides two different series of compounds.
The first series have an alkylene spacer separating the basic center from the 4-aminoquinoline. The second series, which possessed a p-phenoxypropyl spacer, showed a strong inhibitory activity on HMT and the H3R affinity, exceeding that of the first series. Replacing imidazole head with a piperidine ring accompanied by a methylation of the amino functionality improved the inhibitory activity against HMT e. Another approach was attempted on FUB 33 by replacing the aminoquinoline with different heterocycles e.
In contrast to the aminoquinoline, the reported compounds showed moderate to good dual affinities.
Whereas, some compounds showed potent HMT inhibitors, they only showed a moderate H3R affinity and vice versa Apelt et al. The most potent compound in this series was 4- 3-piperidinopropyl phenylether with substituted alkylaminopyridine 37, Figure Tacrine 32 mentioned above is an acetylcholinesterase AChE inhibitor. Together with the symptomatically acting N-methyl-D-aspartate NMDA blocker memantine, tacrine represents the only therapeutic treatment of AD currently available.
AD is a complex neurodegenerative disorder and the most common form of dementia. Therefore, the combination of both activities in a single molecule may offer the desired therapeutic effect with fewer unpleasant side effects considering acetylcholine release in the periphery Fang et al. Using available crystal structure information and applying pharmacophore modeling and docking simulations Bembenek et al.
Some additional in vitro an in vivo studies with these compounds could be of interest to verify the calculated results. In Morini et al. This class is characterized by a rigid biphenyl scaffold and displays nanomolar binding affinities at human and rodent H3R.
Docking the compound 39 into the catalytic cavity of mouse AChE showed similarity to the binding mode, earlier reported for 38, confirming that more rigid and bulky biphenyl scaffolds are tolerated by the AChE active site.
Detailed analysis of biased histamine H4 receptor signalling by JNJ analogues. -
In Bajda et al. In Darras et al. It showed the best activity in two digit nanomolar area for both targets and greater than fold selectivity over the other histamine receptor subtypes.