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Antinociceptive effects of novel histamine H3 and H4 receptor antagonists and their influence on morphine analgesia of neuropathic pain in the mouse.

ABSTRACT: BACKGROUND AND PURPOSE:The histaminergic system is a promising target for the development of new analgesics, as histamine H3 and H4 receptors are expressed in regions concerned with nociceptive transmission. Here we have determined the analgesic effects of new H3 and H4 receptor antagonists in naive and neuropathic mice. EXPERIMENTAL APPROACH:We used chronic constriction injury (CCI) to the sciatic nerve in mice to model neuropathy. Effects of a new H3 receptor antagonist, E-162(1-(5-(naphthalen-1-yloxy)pentyl)piperidine) and H4 receptor antagonist, TR-7(4-(4-chlorophenyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine) were assessed on mechanical (von Frey) and thermal (cold plate, tail flick) stimuli in mice with and without CCI (7 days after injury). Effects of these antagonists on morphine analgesia were also evaluated, along with the possible participation of H1 receptors in their effects. We analysed the compounds in binding and functional cAMP assays at the H3 and H4 receptors and determined metabolic stability. KEY RESULTS:E-162 and TR-7 attenuated nociceptive responses and profound morphine analgesia in males with CCI. These antagonists showed analgesia in naive mice (tail flick test) and produced prolonged analgesia in neuropathic females. E-162-induced analgesia was reversed by pyrilamine, an H1 receptor antagonist. E-162 bound potently to H3 receptors (Ki = 55 nM) and inhibited cAMP accumulation (IC50 = 165 nM). TR-7 showed lower affinity for H4 receptors (Ki = 203 nM) and IC50 of 512 nM. CONCLUSIONS AND IMPLICATIONS:We describe a therapeutic use for new H3 (E-162) and H4 receptor (TR-7) antagonists in neuropathy. Targeting H3 and H4 receptors enhanced morphine analgesia, consistent with multimodal pain therapy.

SUBMITTER: Popiolek-Barczyk K

PROVIDER: S-EPMC6016676 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Antinociceptive effects of novel histamine H<sub>3</sub> and H<sub>4</sub> receptor antagonists and their influence on morphine analgesia of neuropathic pain in the mouse.

Popiolek-Barczyk Katarzyna K Łażewska Dorota D Latacz Gniewomir G Olejarz Agnieszka A Makuch Wioletta W Stark Holger H Kieć-Kononowicz Katarzyna K Mika Joanna J

British journal of pharmacology 20180531 14

<h4>Background and purpose</h4>The histaminergic system is a promising target for the development of new analgesics, as histamine H<sub>3</sub> and H<sub>4</sub> receptors are expressed in regions concerned with nociceptive transmission. Here we have determined the analgesic effects of new H<sub>3</sub> and H<sub>4</sub> receptor antagonists in naive and neuropathic mice.<h4>Experimental approach</h4>We used chronic constriction injury (CCI) to the sciatic nerve in mice to model neuropathy. Effe ...[more]

PMID: 29486058

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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

Antinociceptive effects of novel histamine H3 and H4 receptor antagonists and their influence on morphine analgesia of neuropathic pain in the mouse.

Publications

Antinociceptive effects of novel histamine H<sub>3</sub> and H<sub>4</sub> receptor antagonists and their influence on morphine analgesia of neuropathic pain in the mouse.

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