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Introduction: Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor dysfunction and a diverse range of nonmotor symptoms. Functional relationships between the dopaminergic and histaminergic systems suggest that dual-action pharmaceuticals like AG-0029 (D-2/D-3 agonist/H-3 antagonist) could ameliorate both the motor and cognitive symptoms of PD. The current study aimed to demonstrate the interaction of AG-0029 with its intended targets in the mammalian brain using positron emission tomography (PET).Methods: Healthy male Wistar rats were scanned with a small-animal PET camera, using either the dopamine D-2/D-3 receptor ligand [C-11]raclopride or the histamine H-3 receptor ligand [C-11]GSK-189254, before and after treatment with an intravenous, acute, single dose of AG-0029. Dynamic [C-11]raclopride PET data (60 min duration) were analyzed using the simplified reference tissue model 2 (SRTM2) with cerebellum as reference tissue and the nondisplaceable binding potential as the outcome parameter. Data from dynamic [C-11]GSK-189254 scans (60 min duration) with arterial blood sampling were analyzed using Logan graphical analysis with the volume of distribution (V-T) as the outcome parameter. Receptor occupancy was estimated using a Lassen plot.Results: Dopamine D-2/3 receptor occupancies in the striatum were 22.6 +/- 18.0 and 84.0 +/- 3.5% (mean +/- SD) after administration of 0.1 and 1 mg/kg AG-0029, respectively. In several brain regions, the V-T values of [C-11]GSK-189254 were significantly reduced after pretreatment of rats with 1 or 10 mg/kg AG-0029. The H-3 receptor occupancies were 11.9 +/- 8.5 and 40.3 +/- 11.3% for the 1 and 10 mg/kg doses of AG-0029, respectively.Conclusions: Target engagement of AG-0029 as an agonist at dopamine D-2/D-3 receptors and an antagonist at histamine H-3 receptors could be demonstrated in the rat brain with [C-11]raclopride and [C-11]GSK-189254 PET, respectively. The measured occupancy values reflect the previously reported high (subnanomolar) affinity of AG-0029 to D-2/D-3 and moderate (submicromolar) affinity to H-3 receptors.

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

NLRP3 inflammasome has been implicated in impaired post-injury muscle healing and in muscle atrophy. Histamine receptors play an important role in inflammation, but the role of histamine H3 receptor (H3R) in myocyte regeneration and in the regulation of NLRP3 inflammasome is not known. We studied the effects of H3R signaling on C2C12 myocyte viability, apoptosis, and tumor necrosis factor alpha (TNFα)-induced NLRP3 inflammasome activation during striated myogenic differentiation at three time points (days 0, 3, and 6). Expression of Nlrp3, interleukin-1β (IL-1β), and myogenesis markers were determined. TNFα reduced overall viability of C2C12 cells, and exposure to TNFα induced apoptosis of cells at D6. Activation of H3R had no effect on viability or apoptosis, whereas inhibition of H3R increased TNFα-induced apoptosis. Stimulation of C2C12 cells with TNFα increased Nlrp3 mRNA expression at D3 and D6. Moreover, TNFα reduced the expression of myogenesis markers MyoD1, Myogenin, and Myosin-2 at D3 and D6. H3R attenuated TNFα-induced expression of Nlrp3 and further inhibited the myogenesis marker expression; while H3R -blockage enhanced the proinflammatory effects of TNFα and increased the myogenesis marker expression. TNFα-induced secretion of mature IL-1β was dependent on the activation of the NLRP3 inflammasome, as shown by the reduced secretion of mature IL-1β upon treatment of the cells with the small molecule inhibitor of the NLRP3 inflammasome (MCC950). The activation of H3R reduced TNFα-induced IL-1β secretion, while the H3R blockage had an opposite effect. In conclusion, the modulation of H3R activity regulates the effects of TNFα on C2C12 myocyte differentiation and TNFα-induced activation of NLRP3 inflammasome. Thus, H3R signaling may represent a novel target for limiting postinjury muscle inflammation and muscle atrophy.

Background A method that promotes the retrieval of lost long-term memories has not been well established. Histamine in the central nervous system is implicated in learning and memory, and treatment with antihistamines impairs learning and memory. Because histamine H3 receptor inverse agonists upregulate histamine release, the inverse agonists may enhance learning and memory. However, whether the inverse agonists promote the retrieval of forgotten long-term memory has not yet been determined. Methods Here, we employed multidisciplinary methods, including mouse behavior, calcium imaging, and chemogenetic manipulation, to examine whether and how the histamine H3 receptor inverse agonists, thioperamide and betahistine, promote the retrieval of a forgotten long-term object memory in mice. In addition, we conducted a randomized double-blind, placebo-controlled crossover trial in healthy adult participants to investigate whether betahistine treatment promotes memory retrieval in humans. Results The treatment of H3 receptor inverse agonists induced the recall of forgotten memories even 1 week and 1 month after training in mice. The memory recovery was mediated by the disinhibition of histamine release in the perirhinal cortex, which activated the histamine H2 receptor. Histamine depolarized perirhinal cortex neurons, enhanced their spontaneous activity, and facilitated the reactivation of behaviorally activated neuronal ensembles. A human clinical trial revealed that treatment of H3 receptor inverse agonists is specifically more effective for items that are more difficult to remember and subjects with poorer performance. Conclusions These results highlight a novel interaction between the central histamine signaling and memory engrams.

In an effort to design dual acting compounds enhancing histaminergic neurotransmission in the central nervous system, a novel class of 35 non-imidazole histamine H 3 receptor (H 3 R) antagonists that simultaneously possess strong inhibitory potency on catabolic histamine N -methyltransferase (HMT), have been examined by 3D-QSAR study. For improved understanding, the crucial chemical functionalities for combined H 3 R/HMT activities 3D-QSAR pharmacophore models (H 3 R: R 2 (0.98), Q 2 (0.94), RMSE (0.171); and HMT: R 2 (0.80), Q 2 (0.60), RMSE (0.159) were developed. Pharmacophore for H 3 R antagonistic activity mainly differs from pharmacophore for HMT inhibiting activity in presence of specific lipophilic/steric components of the H 3 R pharmacophore, H-bond accepting components of the H 3 R pharmacophore, H-bond donating components of the HMT pharmacophore, and longer optimal distance between H-bond donor and steric hot spots in the H 3 R pharmacophore than in the HMT pharmacophore. Formed 3D-QSAR models were applied for design of novel piperidino-aminoquinoline hybrids as multitarget H 3 R/HMT ligands with potential impact in therapy of sleep-wake disorders and cognitive impairment. Designed compounds with 3D-QSAR predicted p K i (H 3 R) > 9.6 and (p K i (H 3 R) + pIC 50 (HMT)) > 16.8 were selected for further profiling. Virtual screening of ZINC database is performed against the most promising H 3 R/HMT ligand and top ranked compounds are tested by both 3D-QSAR models.

The histamine H(3) receptor (H(3)R) is an important modulator of numerous central control mechanisms. Novel lead optimizations for H(3)R antagonists/inverse agonists involved studies of structure–activity relationships, cross‐affinities, and pharmacokinetic properties of promising ligands. Blockade of inhibitory histamine H(3) autoreceptors reinforces histaminergic transmission, while antagonism of H(3) heteroreceptors accelerates the corticolimbic liberation of acetylcholine, norepinephrine, glutamate, dopamine, serotonin and gamma‐aminobutyric acid (GABA). The H(3)R positioned at numerous neurotransmission crossroads indicates therapeutic applications of small‐molecule H(3)R modulators in a number of psychiatric and neurodegenerative diseases with various clinical candidates available. Dual target drugs displaying H(3)R antagonism/inverse agonism with inhibition of acetylcholine esterase (AChE), histamine N‐methyltransferase (HMT), or serotonin transporter (SERT) are novel class of procognitive agents. Main chemical diversities, pharmacophores, and pharmacological profiles of procognitive agents acting as H(3)R antagonists/inverse agonists and dual H(3)R antagonists/inverse agonists with inhibiting activity on AChE, HMT, or SERT are highlighted here.

The investigation of novel drug targets for treating cognitive impairments associated with neurological and psychiatric disorders remains a primary focus of study in central nervous system (CNS) research. Many promising new therapies are progressing through preclinical and clinical development, and offer the potential of improved treatment options for neurodegenerative diseases such as Alzheimer's disease (AD) as well as other disorders that have not been particularly well treated to date like the cognitive impairments associated with schizophrenia (CIAS). Among targets under investigation, cholinergic receptors have received much attention with several nicotinic agonists (alpha 7 and alpha 4 beta 2) actively in clinical trials for the treatment of AD, CIAS and attention deficit hyperactivity disorder (ADHD). Both glutamatergic and serotonergic (5-HT) agonists and antagonists have profound effects on neurotransmission and improve cognitive function in preclinical experiments with animals; some of these compounds are now in proof-of-concept studies in humans. Several histamine H3 receptor antagonists are in clinical development not only for cognitive enhancement, but also for the treatment of narcolepsy and cognitive deficits due to sleep deprivation because of their expression in brain sleep centers. Compounds that dampen inhibitory tone (e.g., GABA(A) alpha 5 inverse agonists) or elevate excitatory tone (e.g., glycine transporter inhibitors) offer novel approaches for treating diseases such as schizophrenia. AD and Down syndrome. In addition to cell surface receptors, intracellular drug targets such as the phosphodiesterases (PDEs) are known to impact signaling pathways that affect long-term memory formation and working memory. Overall, there is a genuine need to treat cognitive deficits associated with many neuropsychiatric conditions as well as an increasingly aging population.

Behavioral syndromes are suites of two or more behaviors that correlate across environmental contexts. The aggression–boldness syndrome links aggression, boldness, and exploratory activity in a novel environment. Although aggression–boldness has been described in many animals, the mechanism linking its behavioral components is not known. Here we show that mutation of the gene encoding fibroblast growth factor receptor 1a (fgfr1a) simultaneously increases aggression, boldness, and exploration in adult zebrafish. We demonstrate that altered Fgf signaling also results in reduced brain histamine levels in mutants. Pharmacological increase of histamine signaling is sufficient to rescue the behavioral phenotype offgfr1amutants. Together, we show that a single genetic locus can underlie the aggression–boldness behavioral syndrome. We also identify one of the neurotransmitter pathways that may mediate clustering of these behaviors.

Animal literature suggests an important role for histamine in memory. In humans, this hypothesis has been scarcely tested and results from studies that have addressed this are conflicting. Second, impaired memory performance may be secondary to sedation. This study aimed to determine whether a centrally active antihistamine impairs memory performance and to dissociate such effects from sedation. Eighteen healthy volunteers received single oral doses of dexchlorpheniramine 4 mg, lorazepam 1 mg and placebo in a 3-way, double blind, crossover designed study. The active control lorazepam impaired episodic- and working memory performance and increased sedation, while dexchlorpheniramine only increased sedation.