BACKGROUND: Psychosis is a very common feature of Alzheimer\'s disease (AD) that can emerge as the neurodegenerative disease progresses. The 5-hydroxytryptamine (5-HT2A) receptors are located postsynaptically to serotonergic neurons in the frontal cortex and mediate both excitatory and inhibitory neurotransmissions. However, the effectiveness and tolerance of negative modulators of 5-HT2A receptors in Alzheimer\'s disease psychosis (ADP) are uncertain.
OBJECTIVE: To detect the negative modulators of the 5-HT2A receptor as a cure for ADP.
METHODS: The primary outcome indicator was the total Neuropsychiatric Inventory (NPI) score. Other prognostic indicators included Mini-Mental State Examination (MMSE), the Katz Index of Independence in Activities of Daily Living (KATZ), the discontinuation rate, and adverse events.
RESULTS: Compared to placebo, 5-HT2A inverse agonists significantly reduced the NPI total score, the KATZ and the MMSE score. The pooled odds ratio (OR) was 1.64 (95% confidence interval (95% CI): 1.01-2.65) and the heterogeneity variance was estimated at Tau2 = 0.52 with an I2 value of 90%, a χ2 value of 111.31, p = 0.04, and z-value of 2.01. The risk difference (RD) between the 5-HT2A receptor negative modulators and placebo groups was 0.12 (95% CI: 0.00-0.24) and the heterogeneity was estimated at Tau2 = 0.03, χ2 value of 127.23, degrees of freedom (df) value of 9, I2 value of 93%, z-value of 1.92, and p-value of 0.01 (<0.05).
CONCLUSIONS: Our results suggest that negative modulators of 5-HT2A receptors are beneficial and well-tolerated in the treatment of ADP.

As many, if not most, ligands at G protein-coupled receptor antagonists are inverse agonists, we systematically reviewed inverse agonism at the nine adrenoceptor subtypes. Except for β3-adrenoceptors, inverse agonism has been reported for each of the adrenoceptor subtypes, most often for β2-adrenoceptors, including endogenously expressed receptors in human tissues. As with other receptors, the detection and degree of inverse agonism depend on the cells and tissues under investigation, i.e., they are greatest when the model has a high intrinsic tone/constitutive activity for the response being studied. Accordingly, they may differ between parts of a tissue, for instance, atria vs. ventricles of the heart, and within a cell type, between cellular responses. The basal tone of endogenously expressed receptors is often low, leading to less consistent detection and a lesser extent of observed inverse agonism. Extent inverse agonism depends on specific molecular properties of a compound, but inverse agonism appears to be more common in certain chemical classes. While inverse agonism is a fascinating facet in attempts to mechanistically understand observed drug effects, we are skeptical whether an a priori definition of the extent of inverse agonism in the target product profile of a developmental candidate is a meaningful option in drug discovery and development.

Since years, ligands blocking histamine H3 receptor (H3R) activity (antagonists/inverse agonists) are interesting targets in the search for new cures for CNS disorders. Intensive works done by academic and pharmaceutical company researchers have led to many potent and selective H3R antagonists/inverse agonists. Some of them have reached to clinical trials.
Patent applications from January 2013 to September 2017 and the most important topics connected with H3R field are analysed. Espacenet, Patentscope, Pubmed, GoogleScholar or Cochrane Library online databases were principially used to collect all the materials.
The research interest in histamine H3R field is still high although the number of patent applications has decreased during the past 4 years (around 20 publications). Complexity of histamine H3R biology e.g. many isoforms, constitutive activity, heteromerization with other receptors (dopamine D2, D1, adenosine A2A) and pharmacology make not easy realization and evaluation of therapeutic potential of anti-H3R ligands. First results from clinical trials have verified potential utility of histamine H3R antagonist/inverse agonists in some diseases. However, more studies are necessary for better understanding of an involvement of the histaminergic system in CNS-related disorders and helping more ligands approach to clinical trials and the market. Lists of abbreviations: hAChEI - human acetylcholinesterase inhibitor; hBuChEI - human butyrylcholinesterase inhibitor; hMAO - human monoamine oxidase; MAO - monoamine oxidase.

On 31 March 2016, the European Commission issued a decision for a marketing authorisation valid throughout the European Union (EU) for pitolisant (Wakix) for the treatment of narcolepsy with or without cataplexy in adults. Pitolisant is an antagonist/inverse agonist of the human histamine H3 receptor. The dose should be selected using an up-titration scheme depending on individual patient response and tolerance and should not exceed 36 mg/day. The main evidence of efficacy of pitolisant was based on two Phase III clinical trials. The improvement on excessive daytime sleepiness was shown against placebo in the Harmony I study (-3.33 points; 95% confidence interval (CI) [-5.83; -0.83]; p = 0.024) and in Harmony CTP (-3.41 points; 95% CI [-4.95; -1.87]; p < 0.0001). The daily cataplexy rate in Harmony I improved against placebo with a rate ratio (rR) of 0.38 whilst in the Harmony CTP the ratio of improvement on weekly cataplexy rate against placebo was 0.512. The most commonly reported adverse reactions were headache, insomnia and nausea. This article summarizes the scientific review leading to approval of pitolisant in the EU. The assessment report and product information are available on the European Medicines Agency website (http://www.ema.europa.eu).

BACKGROUND: The transcription factor RORγ plays a critical role in the expression of pro-inflammatory cytokine interleukin IL-17 and is therefore an attractive target for the treatment of inflammatory diseases. Interest in this molecular target has been heightened by the advancement of orally and topically administered RORγ modulators into clinical trials. Areas covered: The present review seeks to summarize published patent applications from assignee companies that have disclosed Investigational New Drug (IND) filings for small molecule RORγ/RORγt antagonists and inverse agonists. Expert opinion: The field of RORγ research is extremely competitive, with the majority of companies targeting psoriasis as the primary disease indication. Vitae Pharmaceuticals is currently the most advanced, with a potential first-in-class oral RORγ-modulator for the treatment of psoriasis. Future efforts will likely expand into potential applications of RORγ-modulators in the lesser explored immune-related areas of rheumatoid arthritis, type 1 diabetes, lupus, and irritable bowel disorder, as well as cancer immunotherapy and castration-resistant prostate cancer.

In the classical two-state model, G protein-coupled receptors (GPCRs) are considered to exist in equilibrium between an active and an inactive conformation. Thus, even at the resting state, some subpopulation of GPCRs is in the active state, which underlies the basal activity of the GPCRs. In this review, we discuss inverse agonists, which are defined as GPCR ligands that shift the equilibrium toward the inactive state and thereby suppress the basal activity. Theoretically, if constitutive activation plays an essential role in the pathogenesis of a disease, only inverse agonists, and not neutral antagonists, can reverse this pathophysiological activation. Although many pharmacological examples of inverse agonism have been identified, its clinical importance is still unclear and debated. Thus, even though inverse agonism of angiotensin receptor blockers (ARBs) has been discussed for more than 10 years, its clinical relevance remains to be completely clarified.

BACKGROUND: Over the past 3 years, several patents appeared dealing with the discovery of compounds able to modulate ghrelin actions: agonists for the treatment of cachexia, as diagnostic agents for GH deficiency or for the increase in gastrointestinal motility, antagonists and inverse agonists as anorexigenic agents for the treatment of obesity and type 2 diabetes. This research has been conducted by several pharmaceutical companies and some compounds have entered clinical trials, but, to date, compounds acting on the ghrelin receptor do not represent clinical options yet.
METHODS: A comprehensive description and categorization of patents related to each type of compounds is provided, together with data related to these compounds that appeared in the scientific literature.
CONCLUSIONS: Ghrelin appears to mediate a myriad of actions, and some of these appear to be due to unknown mechanisms (a second putative ghrelin receptor, putative receptors for unacylated ghrelin); several agonists, antagonists and inverse agonists at ghrelin receptor have been developed but their mechanism of action into CNS is poorly understood. The therapeutic potential of compounds acting on ghrelin receptor is still to be fully assessed, but the results obtained to date are encouraging for the successful clinical translation of compounds able to treat several pathologies.

BACKGROUND: Histamine H3 receptor (H3R) is involved in the central and peripheral regulation of levels of histamine and other neurotransmitters (e.g., acetylcholine, noradrenaline, dopamine or serotonin). H3R antagonists/inverse agonists constitute attractive targets in the search for new drugs. Preclinical data indicate their potential utility in the treatment of various central nervous system (CNS), metabolic, pain and allergic disorders. So far, many structurally diverse H3R ligands have been synthesized and pharmacologically evaluated. Certain compounds have reached clinical trials. The first results from these studies have appeared.
METHODS: The literature covering patent applications (2010 through June 2013) found in the Espacenet database will be reported.
CONCLUSIONS: In comparison with previous years, recently the number of patent applications concerning H3R antagonists/inverse agonists has decreased. The utility of compounds is still being verified in pharmacological studies. The first published results from clinical trials have shown not only positive effects but also emerging drawbacks. So far, BF2.649 is the most advanced in human trials (tiprolisant; Phase III trials). New ligands are being intensively tested in preclinical tests. Thus, it is expected that they will soon undergo clinical trials.

Highly selective angiotensin II (Ang II) type 1 (AT(1)) receptor blockers (ARBs) are now available. The AT(1) receptor is a member of the G protein-coupled receptor (GPCR) superfamily and block the diverse effects of Ang II. Several ARBs are available for clinical use. Most ARBs have common molecular structures (biphenyl-tetrazol and imidazole groups) and it is clear that ARBs have \'class effects\'. On the other hand, recent clinical studies have demonstrated that not all ARBs have the same effects, and some benefits conferred by ARBs may not be class effects, and instead may be \'molecular effects\'. In addition, each ARB has been clearly shown to have specific molecular effects in basic experimental studies, and these effects may be due to small differences in the molecular structure of each ARB. However, it is controversial whether ARBs have molecular effects in a clinical setting. Although the presence of molecular effects for each ARB based on experimental studies may not directly influence the clinical outcome, this possibility has not been adequately evaluated. This review focuses on the class effects versus molecular effects of ARBs from bench to bedside.