Elsevier

Biochemical Pharmacology

Volume 71, Issue 8, 14 April 2006, Pages 1103-1113
Biochemical Pharmacology

Commentary
The challenge of drug discovery of a GPCR target: Analysis of preclinical pharmacology of histamine H3 antagonists/inverse agonists

https://doi.org/10.1016/j.bcp.2005.10.033Get rights and content

Abstract

Although the histamine H3 receptor was identified pharmacologically in 1983, and despite widespread pharmaceutical interest in the target, no compound interacting specifically with this site has undergone successful clinical examination to develop the necessary proof-of-concept data. Therefore, clinical knowledge of the therapeutic potential of H3 receptor antagonists in neuropsychiatric diseases, in metabolic diseases or in sleep disorders has yet to determine if the preclinical data that show broad efficacy in animal models of the aforementioned states are relevant to current unmet medical needs. H3 receptors are complex, with species-related sequence differences that impact pharmacological responses. The receptors have a complex gene organization that provides opportunity for multiple slice isoforms, most of which remain poorly characterized even within a species. H3 receptors are constitutively active, although the extent of this could vary either between species and/or receptor splice isoforms, both of which may provide opportunity for preferential coupling to different G-proteins. Thus, it is not surprising that the pharmacological effects of known H3 ligands are complex and diverse, since these agents may act both as agonists and antagonists in different systems. Moreover, other compounds show inverse agonism in some models but neutral antagonist activity in others. Some of this diversity may be related to different ligand-dependent receptor activation states or to the effects of key amino acids important for ligand recognition. This commentary provides an overview of these complexities as applied to the H3 receptor and the challenges these intricacies create for drug discovery.

Introduction

Drugs targeting G-protein coupled receptors (GPCRs) represent one of the most successful classes of pharmaceutical remedies known. In recent years, it was estimated that as many as 50% of available drugs act directly via stimulating or blocking GPCRs [1]. Among such drugs are the antiallergy medications, such as the classical “antihistamines” (e.g., diphenhydramine), non-sedating second-generation compounds (astemizole, terfenadine, loratidine), or third-generation compounds (norastemizole, fexofenadine, desloratidine) and antiulcer medications (cimetidine, ranitidine, famotidine). These compounds are antagonists of H1 and H2 receptors, respectively. Since the 1983 discovery of the H3 receptor [2] and the 2000 identification of the H4 receptor [3], it has become clear that histamine (HA) has a total of four known GPCR targets, and a number of pharmaceutical companies are actively pursuing novel compounds targeting these newest histamine receptors for various therapeutic indications.

From studies of the H3 receptor, a number of novel findings have emerged, suggesting that the H3 receptor has many levels of complexity, many of which have direct implications for the process of drug discovery. Novel compounds have been identified that interact with H3 receptors, arising from diverse research programs. Yet, to date, no compounds have successfully met the challenges of the drug development process to allow sufficient clinical evaluation and, thereby, enable proof-of-concept for the various therapeutic indications that have been proposed for H3 receptor agonists and antagonists. This commentary focuses on how aspects of H3 receptor complexity have led to advances in our knowledge of receptor pharmacology and the advancement of compounds with ever improving drug-like properties toward eventual clinical use, with most examples taken from the experiences of colleagues at Abbott Laboratories.

Section snippets

Species-dependent H3 receptor pharmacology: implications for H3 antagonist drug discovery

Between its discovery in 1983 [2] and 1999, attempts to clone the H3 receptor were unsuccessful until Lovenberg et al. correctly identified and functionally characterized the human H3 receptor [4]. In retrospect, homology-searching strategies, as had been performed successfully for many other biogenic amine receptors, failed because the H3 receptor gene and protein are so distinct from the previously cloned H1 and H2 receptors [5]. The rapid success (within 12 months) by multiple investigators

H3 receptor splice isoforms

Comparison of the gene and protein sequences of H3 receptors from various species indicated the presence of introns in several, but not all species (for review, see Ref. [26]). While the intricacies and variations of these splice isoforms are beyond the scope of this commentary, of the many isoforms identified in the various species studied few have been characterized pharmacologically. Some are presumed to be inactive in their own right, because they are truncated at portions of the receptor

H3 receptor antagonists and compound-related adverse effects

With regard to our prototypic lead compounds, A-331440 and A-349821, additional challenges thwarted their advancement into clinical trials. For A-331440, favorable characteristics included the balanced affinity at human and rat H3 receptors, sustained efficacy in antiobesity tests, ready access to the CNS (generally in excess of blood levels by more than 100-fold) providing low circulating levels that were expected to reduce the risk of any adverse effects. However, A-331440 was genotoxic in an

Enhancement of drug-like properties of H3 receptor antagonists

Medicinal chemists often turn to one or more of several key concepts to increase the likelihood of identifying drug-like molecules. We had previously avoided imidazole-based compounds because of such reasoning, since many imidazoles are potent inhibitors of drug-metabolizing CYP enzymes, leading to the potential for drug–drug interactions, or inhibition of adrenal steroid production [41]. A recent pragmatic example demonstrates the importance of such drug–drug interactions. Augmentation of the

Further H3 receptor antagonist considerations: repeated dosing efficacy and inverse agonism

While many selective antagonists for the H3 receptor have now been described of quite diverse chemical structure, there are far less detailed biological data reported for most of these compounds. Moreover, their preclinical evaluation has generally depended upon the interests of the research teams, i.e., models of sleep or cognitive performance or in feeding and weight loss, among others. Of course, this reflects the lack of clinical validation of the therapeutic utility of H3 receptor

Conclusions

The aforementioned findings of species-related sequence differences, pharmacological differences, splice isoforms, constitutive activity, desensitization mechanisms, hetero-, and autoreceptor effects all add to the routine concerns in drug development of safety issues, drug metabolism issues, and pharmacological activity that seem particularly byzantine in the case of the histamine H3 receptor. Given these complexities, it is less surprising, perhaps, that no compound in this class has provided

Acknowledgements

Since the submission of this paper, Dr. Art Hancock has unfortunately passed away. He wished to thank Marlon Cowart, Timothy Esbenshade, and Gerard Fox for thoughtful discussion, comments and ideas and both Gerard Fox and Kaitlin Browman for the insights, data and preparation of Fig. 3. Furthermore, the help of colleagues within Neuroscience Discovery, Metabolic Diseases Research, Integrative Pharmacology and Exploratory Kinetics who have synthesized or evaluated the numerous compounds in a

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    Correspondence to: Tim Esbenshade. Tel.: +1 847 935 4727; fax: +1 847 937 9195.

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