Drugs which act at the H1 receptor have been known for many years. Discovery of the first HA antagonist (over fifty years ago) led to an increased understanding of anaphylaxis and allergy, set the stage for demonstrating the likely existence of more than one type of HA receptor, and indirectly led to the subsequent development of phenothiazines and tricyclic antidepressants (Green 1983). Hundreds of the so-called 'classical' or first-generation H1-antagonists have been developed and many are still in clinical use. These compounds all share two aromatic rings and a basic amine moiety, and have been further divided into five chemical classes. Members of this group include diphenhydramine, d-chlorpheniramine, and pyrilamine. All of these drugs have good brain-penetrating characteristics. Pyrilamine (also named mepyramine) remains a prototype H1 antagonist with very high affinity and excellent selectivity for the H1 receptor. Although all of the first-generation compounds have some local anesthetic and anti-muscarinic properties, for pyrilamine these occur at concentrations substantially greater than those acting at the H1 receptor. In cases where H1 antagonists have activity but the role of the H1 receptor is uncertain, d- and l-chlorpheniramine can be used to classify HA responses, since these compounds share many activities but differ by several hundred-fold in their anti-H1 activity (Hill et al. 1997). The classical H1 antagonists have very good anti-allergic properties, and are also used widely as over-the-counter sleep aids.
The sedative properties of the classical H1 blockers limit their day-time use and have fostered the development of the second-generation or 'non-classical' H1 antagonists. These compounds include astemizole, cetirizine, terfenadine, fexofenadine, and loratid-ine (Fig. 17.4). Several of the second-generation H1 antagonists enjoy wide popularity and have good anti-allergic activity. As compared with classical H1 antagonists, these newer drugs show much lower brain penetration, commensurate with greatly reduced sedative side effects. Although differences in brain versus peripheral H1 receptor affinity for these drugs had been suggested to account for the peripheral selectivity of these compounds, this has not been validated (Ter Laak et al. 1993), and there is no convincing evidence for the existence of more than one type of H1 receptor. Some of the early second-generation compounds (e.g. terfenadine) were found to act at cardiac potassium channels, leading to rare but dangerous toxicity (Woosley 1996). Many of the second-generation H1 antagonists are metabolites of other H1 antagonists. For example, cetirizine, fexofenadine, and desloratidine are active metabolites of hydroxyzine, terfenadine, and loratidine, respectively. Detailed models of the interactions between H1 antagonists and the H1 receptor have been developed (Ter Laak etal. 1995).
Sir James Black and colleagues synthesized and characterized the first H2 receptor antagonists, unequivocally demonstrating the existence of more than one type of HA receptor (Black et al. 1972). The work showed clearly a physiological role for gastric HA and revolutionized the treatment of peptic ulcer disease. Presently, there are four H2 antagonists in wide clinical use: cimetidine, ranitidine, famotidine, and nizatidine. Surprisingly, cimetidine's Kd on the H2 receptor is only 0.8 ^M (Hill et al. 1997), yet the drug has been used successfully by millions of patients with only a few side effects. Cimetidine is known to inhibit some forms of cytochrome P450, which can lead to clinically significant drug-drug interactions (Furuta et al. 2001). Many other non-H2 actions of cimetidine have been found at higher drug concentrations (see table 3 in Hough et al. 1997). Because of its low potency and non-H2 actions, cimetidine is not a good experimental agent to study H2 receptor actions. Ranitidine (Kd = 63nM (Ganellin 1982) or famotidine (Kd = 17nM (Cooper etal. 1990)) are good alternatives with much higher H2 potency and lacking many of cimetidine's non-H2 actions. Among the most potent known H2 antagonist is iodoaminopotentidine (Kd = 30 nM, (Hirschfeld et al. 1992)), which, as mentioned, is a very useful tool for receptor studies, but has also been used to study H2 receptor function. A very large number of H2 antagonists have been developed over the two decades which followed the commercial success of this class of drugs, and a diverse structure-activity relationship (SAR) has evolved (Cooper etal. 1990). Newer H2 antagonists continue to be developed (Anglada et al. 1997; Kijima et al. 1998).
Because many H2 antagonists retain HA's polar imidazole group (or another isosteric polar group), most H2 antagonists do not reach the CNS after systemic dosing. Thus, intracerebral or intraventricular injections of H2 antagonists were needed to study H2 receptor functions in the CNS. To circumvent this, Young et al. (1988) described the development and characterization of zolantidine, a brain-penetrating H2 receptor antagonist (Calcutt et al. 1988). Although never developed for human use, zolantidine is active in vivo and has been used to investigate many brain roles for H2 receptors.
d-Ch l orpheniramine
Fig. 17.4 Structures of HA antagonists.
Fig. 17.4 Structures of HA antagonists.
Discovery of the H3 receptor followed the observation that extra-synaptosomal HA was capable of downregulating HA synthesis and release. Initial characterization of this response showed it to be distinct from both H1 and H2 receptors (Arrang etal. 1983). The unequivocal existence of the new receptor was established by development of thioperamide, a potent and selective H3 antagonist (Arrang etal. 1987). The activity of thioperamide in a many different biochemical, physiological, and behavioural assays has documented the significance of HA and the H3 receptor in the nervous system, and thioperamide remains a prototype H3 antagonist. However, at concentrations higher than the H3 Kd, thioperamide can act at other receptors, including 5HT3, and H4 (Hough, 2001; Leurs et al. 1995c). Other findings suggest that thioperamide may also act directly to inhibit GABA transport (Yamamoto et al.
1997) and drug metabolizing enzymes (Alves-Rodrigues et al. 1996). Binding experiments with the cloned H3 receptors have confirmed that thioperamide has a high affinity for the rat receptor (Ki = 4 nM), but shows a ten-fold lower affinity for the human receptor (Lovenberg et al. 2000), even though these receptors differ by only a few amino acids (Ligneau et al. 2000). As mentioned above, there is evidence that H3 receptors are constitutively active in vivo, and thioperamide (and many other H3 antagonists) may behave in vivo as an inverse agonist (Morisset et al. 2000). Systematic variation in structures of H3 agonists led to the development of the H3 antagonist clobenpropit, which can be viewed as an isothiourea congener of thioperamide (van der Goot et al. 1992; Leurs et al. 1995b). Clobenpropit has very high affinity for both the rat and the human H3 receptor (Ki = 0.4-0.6 nM, Lovenberg etal. 2000).
The SARs derived from early studies of thioperamide-like drugs suggested the existence of fairly stringent structural requirements for blocking H3 receptors, including an imidazole nucleus, a conformationally restricted side chain, a thiourea polar group, and a hydrophobic tail (Leurs and Timmerman 1992; Leurs etal. 1995b). However, more recent work has shown the existence of a much broader SAR for H3 antagonists, which has led to a large expansion of known active structures. Development of GT-2016 (Tedford et al. 1995) eliminated the thiourea group of thioperamide which was thought to be the cause of liver toxicity after chronic administration. Discovery of ciproxifan (Ligneau etal. 1998) demonstrated a potent H3 antagonist lacking the polar group. Remarkably, potent H3 antagonists have been more recently discovered which have no heteroatom whatsoever in their side chain. These include GT-2331 (Tedford etal. 1999) and several others (Stark etal. 1998;DeEsch etal. 1999). Newer H3 antagonists continue to be developed by several academic and corporate laboratories. Most interesting among these compounds is the discovery that potent H3 antagonists can be synthesized which lack imidazole (Ganellin etal. 1998; Meier etal. 2001; Bennani etal. 2001; Carruthers et al. 2002). Removal of imidazole seems to be desirable in order to improve brain penetration and also minimize H4 antagonist activity, which is a feature of many imidzole-containing H3 antagonists (Liu etal. 2001a). Molecular models of H3 antagonist action have been developed and tested recently (De Esch et al. 2001).
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