The histamine H4 receptor: from orphan to the clinic

Abstract

The histamine H4 receptor (H4R) was first noted as a sequence in genomic databases that had features of a class A G-protein coupled receptor. This putative receptor was found to bind histamine consistent with its homology to other histamine receptors and thus became the fourth member of the histamine receptor family. Due to the previous success of drugs that target the H1 and H2 receptors, an effort was made to understand the function of this new receptor and determine if it represented a viable drug target. Taking advantage of the vast literature on the function of histamine, a search for histamine activity that did not appear to be mediated by the other three histamine receptors was undertaken. From this asthma and pruritus emerged as areas of particular interest. Histamine has long been suspected to play a role in the pathogenesis of asthma, but antihistamines that target the H1 and H2 receptors have not been shown to be effective for this condition. The use of selective ligands in animal models of asthma has now potentially filled this gap by showing a role for the H4R in mediating lung function and inflammation. A similar story exists for chronic pruritus associated with conditions such as atopic dermatitis. Antihistamines that target the H1 receptor are effective in reducing acute pruritus, but are ineffective in pruritus experienced by patients with atopic dermatitis. As for asthma, animal models have now suggested a role for the H4R in mediating pruritic responses, with antagonists of the H4R reducing pruritus in a number of different conditions. The anti-pruritic effect of H4R antagonists has recently been shown in human clinical studies, validating the preclinical findings in the animal models. A selective H4R antagonist inhibited histamine-induced pruritus in health volunteers and reduced pruritus in patients with atopic dermatitis. The history to date of the H4R provides an excellent example of the deorphanization of a novel receptor and the translation of this into clinical efficacy in humans.

Aryl-1,3,5-triazine ligands of histamine H4 receptor attenuate inflammatory and nociceptive response to carrageen, zymosan and lipopolysaccharide

“…This compound, along with other H 4 R antagonists, has shown activity in models of asthma, dermatitis, pain, and pruritus among others [17–20]. It supports the hypothesis that the histamine H 4 R offers a great potential for new therapeutic strategies for the treatment of inflammation-based diseases.…”

“…The subsequent discovery of the potent and selective H 4 R antagonist-JNJ7777120 [29]-enabled studies on physiological and the pathophysiological functions of H 4 R and provided the first evidence that H 4 R blockade could result in anti-inflammatory effect [30]. In recent years, scientists reported that H 4 R antagonists are effective in models of asthma, dermatitis, arthritis, pain, pruritus and colitis [17–20, 31–33]. …”

Genetic Variation in the Histamine Production, Response, and Degradation Pathway Is Associated with Histamine Pharmacodynamic Response in Children with Asthma

“…Therefore, genetic variation of the HRH4 receptor is likely to have more far reaching effects than stimulating allergic response and may lead to overall alterations in the immunologic response among those with asthma and allergic disease. Attenuation of response with HRH4 inverse agonist agents, currently in clinical trials, may be even more beneficial in these patients in the treatment of asthma (Thurmond, 2015). …”

The histaminergic system as a target for the prevention of obesity and metabolic syndrome

“…H 1 Rs and H 2 Rs are well-established drug targets, and antagonists of these receptors have been successfully used as blockbuster drugs for treating allergic conditions and gastric ulcers. The H 4 R has a primary role in inflammatory functions, making it an attractive target for the treatment of asthma and refractory inflammation (Thurmond, 2015). Nevertheless, there is evidence that antagonism of H 4 Rs exacerbates clinical and pathological signs of experimental autoimmune encephalomyelitis (Ballerini et al, 2013) thus suggesting caution in the clinical use of H 4 R antagonists (Passani and Ballerini, 2012).…”