histamine derivatives resulted in 2-(3-bromophenyl)histamine (10.49) and its trifluoromethyl analogue (10.50). These compounds have 112% and 128% relative activity, respectively. Compounds (10.49) and (10.50) make the H1-receptor— mediated biological functions in experimental characterization much more precise than former tools.

Most people have allergic and inflammation reactions on their mind when thinking of histamine. Compounds preventing this response to histamine are the first so called "antihistamines". These H1-receptor antagonists are among the most widely used medications in the world. In contrast to histamine these agents are generally lipophilic compounds due to aromatic moieties. A small chain connects this aromatic ring structure to a protonable basic center, in most cases a tertiary nitrogen. One of the most potent and selective antagonists used pharmacologically is mepyramine (pyrilamine, 10.51). In radiolabelled form (3H, 11C) it can also be used for binding characterizations in vitro as well as in vivo. One of the most useful [125I]iodinated H1-receptor antagonists is iodobolpyramine (10.52) which could be easily prepared in a reaction with a radiolabelled precursor. Many other compounds have been developed subsequently of which chlorpheniramine (10.53) and diphenhydramine (10.54) are two examples.

(10.51); mepyramiiie

Chlorpheniramine shows a stereoselective effect presenting higher antagonist activity with its -enantiomer (eutomer). These Hrreceptor antagonists of the first generation have a number of side effects which led to further developments of neuroleptics (chlorpromazine), antidepressants (amitriptyline, doxepin) or anticholinergic agents (trihexyphenidyl, biperiden). The most common central side-effect of lipophilic Hrreceptor antagonists is sedation. This property is now exploited with diphenhydramine and promethazine (10.55) as a main indication. Sedation and atropine-like side-effects led to the next generation of Hrreceptor antagonists. Ketotifen (10.56) is a potent Hrreceptor antagonist and possesses antagonist activity to other allergy-inducing agents such as bradykinin or serotonin. This is an example of an antihistamine with additional o

(10.56); Ketotifen

(10,57); Terfenadine

aslemizole antiallergic activity. Terfenadine (10.57) and astemizole (10.58) are not capable of readily penetrating the blood-brain barrier. Due to this lack of central effects in therapeutic dosage as a consequence of pharmacokinetic differences, (10.57), (10.58) and other newer antihistamines (loratidine, cetirizine, levocabastine) may have advantages in their side-effect profile.

10.3.3 H2-receptors

Structural similarities of the H2-receptor agonists dimaprit (10.59) and amthamine (10.60) to histamine (10.45) are obvious. In addition to the protonated side-chain nitrogen the structures are capable of making hydrogen bonds and of undergoing a 1,3-prototropic tautomerism like the imidazole moiety. The isothiourea and the aminothiazole moieties may be considered as bioisosteres of imidazole in this particular case. These compounds are roughly in the same activity range as histamine. Elongation of the alkyl chain and variation of the amino functionality to a strongly basic substituted guanidine group led to a strong increase in H2-receptor agonist activity. Impromidine (10.61) which contains two imidazole fragments is 48 times more potent than histamine. The imidazolylpropylguanidine group seems to be responsible for agonist binding whereas the other part of the molecule (cimetidine part, cf. 10.63) contributes additional binding. This binding is improved by a diary lalkyl structure such as in arpromidine (10.62). On cardiac H2-receptors this compound is about 100 times more potent than histamine, but shows different activity


{10.63): cimetidine

(10.64); ranitidine with different preparations of H2-receptors giving a hint for H2-receptor subpopulations. Thereby, the "fluoropheniramine" partial structure of (10.62) (cf. 10.53) also incorporates H1-receptor antagonist activity.

The partial structure of impromidine (10.61) that enhances activity is the main structural element of cimetidine (10.63), the first world-wide marketed H2-receptor antagonist. The guanidine group is substituted by a cyano group which reduces the basic properties of this moiety and leads to a highly polar group. The basic imidazole ring connected by a flexible chain to a polar group which is uncharged under physiological conditions leads to H2-receptor antagonists. The imidazole moiety seems to be responsible for the inhibition of cytochrome P450-dependent reactions leading to unwanted side-effects with co-medications in man. Therefore, new developments replaced the imidazole ring bioisostere with a basic substituted furan (ranitidine, 10.64) and thiazole (famotidine) rings or a basic substituted phenoxyalkyl moiety (roxatidine acetate, 10.65; iodoaminopotentidine, 10.66; zolantidine, 10.67). H2-Receptor antagonists are used for the treatment of conditions associated with gastric hyperacidity such as peptic ulcer disease or reflux oesophagitis. The new compounds have a high therapeutic index showing low incidence of side-effects. One of the most potent H2-receptor antagonists is iodoaminopotendine (10.66). This compound and a related azido derivative were used in radiolabelled form for autoradiographic localization, specific binding studies and photoaffinity labelling of cerebral H2-receptors. All these compounds except (10.65)

possess a cyanoguanidine, nitroethenediamine or comparable "urea equivalents" as a structural alternative for the polar group. Therefore, they do not readily cross the blood-brain barrier. No important central effects could be detected with these drugs in vivo. Their physicochemical properties have to be taken into account. Drug design to optimize the partition coefficient, ionization constant, and molecular size with retention of H2-receptor antagonist activity led to zolantidine which is capable of penetrating into the central nervous system. Hallucinatory effects of some H2-receptor antagonists when given in high dosage and the control of nociceptive responses may be clarified by behavioural experiments with zolantidine.

10.3.4 H3-receptors

The function of histamine as a neurotransmitter, in addition to its autacoid function, was strengthened by the discovery of the histamine H3-receptor. Histamine shows selectivity for the H3-receptor displaying a higher activity at H3- rather than at H1- and H2-receptors (H3, pD2 7.2; H2, pD2 6.0; H1, pD2 6.85). All H3-receptor ligands with high affinity known so far possess an imidazole ring. Any replacement study leads to a dramatic decrease in affinity. Even substitution by small methyl groups on the imidazole ring decreases H3-receptor affinity (cf. 10.63). On the other hand, methylation on the side-chain increases agonist activity in particular cases. Methylation on the side-chain nitrogen resulted in the H3-receptor agonist Na-methylhistamine (10.68). Although this compound is often used in tritium-labelled form in H3-receptor binding studies it shows some remarkable affinity at H1- and H2-receptors. The use of the chiral methylated histamine derivative [3H] R)-a-methylhistamine should be favoured over other commercially available [3H]labelled H3-receptor agonists for these investigations. The reason for this preference is that the selectivity of side-chain methylated histamine derivatives were increased by R)-a-methylhistamine (10.69), now the standard agonist for histamine H3-receptors, and was

furthermore increased with (a.ft,pS)-a,p-dimethylhistamine (10.70). Despite their structural similarity these compounds show low activity at H1- and H2-receptors but compared to histamine they exhibit 15 and 18 times the H3-receptor agonist activity, respectively, displaying impressive receptor selectivity. The side chain-branched histamine derivatives show a high degree of stereoselectivity. In all cases the enantiomer with the same relative configuration in the a-position as L-histidine is the eutomer. The eudismic ratio of (10.69) compared to its (S^-enantiomer (distomer) is about 130. Even the iMdazolylmethylpjrrolidine derivative (immepyr, 10.71) shows this stereoselectivity. A comparable compound containing an achiral piperidinylmethyl moiety (immepip) was also developed recently. One of the most potent H3-receptor agonists so far is the imidazolylethylisothiourea derivative (10.72, imetit). Replacement of the side-chain nitrogen by the polar isothiourea moiety, cationic under physiological conditions, leads to improved receptor activity. The sulfur atom in imetit is not critically important and may be replaced by oxygen or methylene. Recent studies with molecular modelling methods showed that all these H3-receptor agonists could be superimposed on one pharmacophore model displaying similar molecular interaction patterns. Unfortunately all these ligands display similar physicochemical properties. They are extremly hydrophilic compounds which do not easily cross the blood-brain barrier and reach the central nervous system (CNS), the area with the highest H3-receptor density. It is notable that the well investigated (R)-a-methylhistamine (10.69) is a good substrate for the inactivating enzyme histamine methyltransferase. Clinical trials were not as promising as the first pharmacological experiments. Pro-drugs of (10.69) were designed to prepare lipophilic compounds which could easily penetrate biological membranes besides not being a substrate for the inactivating enzyme. Compound (10.73) is the lead structure for pro-drugs of (10.69). The liberation of the active drug (10.69) depends on chemical hydrolysis of the azomethine bond. Depending on the substitution pattern of the benzophenone pro-moiety the compounds could be targeted to central or peripheral tissues. High plasma and CNS levels of the biologically highly active R)-a-methylhistamine could be achieved by this approach for a prolonged duration.

Histamine derivatives with larger substituents on the side-chain Na nitrogen lead to partial agonists, and further increasing the size of the substituents leads to histamine H3-receptor antagonists. This transition from agonist to antagonist was extensively shown with histamine derivatives, but the same is true for derivatives of imetit (10.72). Clobenpropit (10.74) is in vitro one of the most potent H3-receptor antagonists obtained by this approach. The first compounds detected as H3-receptor antagonists were compounds from the line of H2-receptor antagonists. Burimamide (10.75) which was used as the first "selective" H2-receptor antagonist for the characterization of H2-receptors was ironically also used for the characterization of H3-receptors later on. The Hrreceptor agonist betahistine (10.47) shows some, while the H2-receptor agonists impromidine (10.61) and arpromidine (10.62) show high H3-receptor antagonist activity. Once more the imidazole structure like that in histamine seems to be an essential component of highly potent H3-receptor ligands. With the optimization of the thiourea derivative (10.75) a new rigid piperidino and a cyclohexyl moiety was


introduced. The resulting thioperamide (10.76) was the first highly potent and selective H3-receptor antagonists. Therefore, (10.76) is now the standard antagonist. A general structural pattern for activity was developed using different series of antagonists. A nitrogen-containing heterocycle (mainly imidazole) is connected via a chain to a polar group; this structure seems to be essential for a potent antagonist interaction with H3-receptors. A lipophilic residue, linked to the polar group

by a spacer seems to enable the molecule to reach additional binding areas, e.g. a hydrophobic pocket on the receptor, so that the H3-receptor antagonist activity of the resulting molecule increases. This structural pattern was used to design a new H3-receptor radioligand with high potency and selectivity. In contrast to the former antagonists possessing a polar group easily able to form hydrogen bonds, the resulting iodoproxyfan (10.77) has an ether functionality. This structure is suited for hydrogen bonding to a limited extent only. This seems necessary to lower the unspecific binding of a useful radioligand. [125I]lodoproxyfan fulfills all criteria for a radioligand such as high activity, selectivity and specificity as well as saturable and reversible binding.

Although radioligands are useful for different pharmacological experiments the development of therapeutically acceptable drugs is a different prospect. Recently, a new class of imidazolylalkyl carbamates were developed possessing high H3-receptor antagonist activity in vivo following oral administration. A-Fluorophenyl carbamate (10.78) is one potent lead in this series. Depending on the substitution pattern of the phenyl ring the pharmacokinetic properties could be varied with retention of the antagonist activity. This approach seems to be very promising in developing the first potentially useful H3-receptor antagonists. But the therapeutic indication is not totally clear at present. Different psychic disorders or diseases, e.g. epilepsy, stress, food intake, sleeping, vertigo or Morbus Alzheimer's disease, seem potential targets for H3-receptor antagonists. Influencing the histaminergic neurotransmitter system seems to be an attractive new

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