Agonists

In contrast to the plethora of drugs available to selectively block H1 receptors, a relatively small number of drugs have been found which are able to selectively activate these receptors. The 2-pyridinyl and 2-thiazolyl isosteres of HA show some selectivity toward H1 versus other HA receptors (Hill et al. 1997), but these drugs are less potent than HA at H1 receptors, and can have non-HA actions in vivo. Discovery that 2-substituted HA derivatives showed H1-selectivity and retained potency led to development of 2-(3-(trifluoromethyl) phenyl)-HA as an experimental H1 agonist (Leschke et al. 1995).

It is interesting to note that other 2-substituted phenylhistamine derivatives with H1 agonist activity were found to activate G proteins by an H1-receptor independent mechanism (Seifert etal. 1994b). Subsequent carefully-performed experiments showed the mechanism to be a mastoparan-like direct activation of G proteins (Detert et al. 1995), an action which depends on the detergent-like cationic-amphiphilic properties of some of these agents. This mechanism is thought to account for the mast cell HA-releasing properties of many compounds, including local anesthetics, contrast media, opioids, neuromuscular blockers, even some H1 antagonists (Burde etal. 1996; Klinker and Seifert 1997).

More recent exploration of 2-substituted HA derivatives has led to the discovery of histaprodifen and methylhistaprodifen (Fig. 17.3), which are highly selective and potent H1 agonists (Elz et al. 2000). These compounds show at least ten-fold selectivity for the H1 receptor as compared with several other receptors (Elz et al. 2000) and have excellent H1 activity in vivo (Malinowska et al. 1999). Although further characterization of the selectivity of these compounds is needed, they show great promise as emerging tools for exploring drug action and physiology of the H1 receptor.

Dimaprit, the first selective H2 agonist (Parsons et al. 1977), has been widely used in vivo and in vitro. Although not an imidazole, the compound closely mimics imidazole tautomer-ism, a characteristic thought to be essential for H2 receptor activation (Leurs et al. 1995 b). Dimaprit has an H2 potency approximately equal to that of HA, but demonstrates extraordinary selectivity as compared with the other HA receptors (Hill et al. 1997). Combinations of modelling and testing of dimaprit derivatives led to development of amthamine, another highly selective and slightly more potent H2 agonist which shows good in vivo activity (Leurs et al. 1995b). An even more potent H2 agonist is impromidine (Leurs et al. 1995b; Hill et al. 1997), which is 48 times more potent than HA on the guinea-pig atrial H2 receptor. However, impromidine has much lower potency on other H2-receptor responses, suggesting a limited intrinsic efficacy for this compound. It must be kept in mind that impromidine and dimaprit can also act as H3 antagonists (Arrang et al. 1983; Hill et al. 1997). Impromidine can also block H1 receptors at higher (i.e. micromolar) concentrations (Hill et al. 1997). Administered in vivo, dimaprit and amthamine have been shown to produce CNS and cardiovascular effects which are distinct from H2 receptor actions (Coruzzi et al. 1996; Swaab etal. 1992).

The discovery that R-a-methylhistamine is a potent and selective agonist which can inhibit the neuronal release of HA was a cornerstone in establishing the existence of the H3 receptor (Arrang et al. 1983). This compound has not only served as a critical radioligand for characterizing the receptor, but also as a powerful in vivo tool for revealing H3 functions. It should be noted that although R-a-methylhistamine has very high selectivity for the H3 receptor, it

,NH2

Histamine

2-(2-Thiazolylethyl)amine

2-(2-Thiazolylethyl)amine

Histaprodifen

H3C.

,NH2

Histaprodifen

HN^N

Impromidine

sJC>

H3C.

CH3 Amthamine

H2N NH

Dimaprit

H3" H

R-(alpha)-methylhistamine

Immepip

Dimaprit

BP2-94 (H3Prodrug)

Fig. 17.3 Structures of HA agonists.

BP2-94 (H3Prodrug)

Fig. 17.3 Structures of HA agonists.

Immepyr

also has significant Hi activity which can be demonstrated in vivo (Hey et al. 1992; Endou et al. 1994; Jennings et al. 1996; Hegde et al. 1994). The compound can also act at the adrenergic a2 and H4 receptors.

Like HA, R-a-methylhistamine is highly polar and shows minimal (but measurable (Taylor et al. 1992)) brain penetration after systemic dosing. In addition, R-a-methylhistamine in plasma was rapidly inactivated in man by histamine N-methyltransferase following systemic administration (Rouleau et al. 1997). Although it was known that this compound was a substrate for histamine N-methyltransferase (Hough et al. 1981), the short half-life seen in man was not predicted in animal studies due to a species difference in enzyme activity. To circumvent the rapid metabolism and poor brain penetration of R-a-methylhistamine, prodrugs of this H3 agonist (e.g. BP2-94) have been synthesized and tested (Krause et al. 1995). This pro-drug approach succeeded in achieving more peristent levels ofthe active metabolite

R-a-methylhistamine, although neither BP2-94 nor its active metabolite was detected in the brain (Rouleau etal. 1997).

Several other H3 agonists have been described which are closely related to the HA/R-a-methylhistamine structure. These include imetit (Garbarg et al. 1992; van der Goot et al. 1992), immepip (Vollinga et al. 1994), and immepyr (Shih et al. 1995). Unlike R-a-methylhistamine, these newer H3 agonists lack significant H1 activity and are also not substrates for histamine N-methyltransferase. It is interesting to note that although immepip and imetit are both imidazoles with ammonium-containing side chains at physiological pH (and thus might not be expected to penetrate the brain (Garbarg etal. 1992)), there is evidence that these drugs act at brain H3 receptors after systemic administration (Garbarg et al. 1992; Blandina etal. 1996; Jansen etal. 1998). Another HA analogue, impentamine, has very high affinity for H3 receptors (Vollinga et al. 1995). This drug behaved as a partial agonist in brain H3 assays, but as an antagonist on the peripheral H3 receptor bioassay (Leurs et al. 1996). In addition, impentamine and the other HA homologues show different potencies on the brain and peripheralH3 receptors (Leurs etal. 1996; Harper etal. 1999). Impentam-ine showed nearly a ten-fold difference in agonist potencies among the cloned H3 subtypes found in the rat brain (Drutel et al. 2001), which may be relevant to these observations. More recently, ether and carbamate derivatives have been discovered which behave in vivo as full H3 agonists, yet these drugs completely lack side chain amines, and thus cannot exist as monocations (Sasse et al. 1999). Since all known agonists acting at HA receptors were previously thought to require this cation (Hough 1999; Leurs et al. 2000; Lovenberg et al. 1999), this is of considerable interest.

Because the discovery of H4 receptors is so recent, potent drugs capable of selectively activating or inhibiting these receptors have not yet been found (Hough 2001). The high affinity H3 agonists all activate the H4 receptor, but with a reduced potency. The H3 antagonist thi-operamide has a 5-10-fold lower activity at the H4 as compared with the H3 receptor. Other H3 antagonists such as clobenpropit show partial agonist activity at the H4 receptor. It is clear that H3 and H4 activities can be separated, since a recently-described non-imidazole H3 antagonist was shown to lack activity at H4 (Liu et al. 2001a). The emerging pharmacology of the H4 receptor was recently reviewed (Hough 2001).

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