Biomedical Engineering Reference
In-Depth Information
O
HN
N
H
Imidazole
acetaldehyde
HDC
NH 2
NH 2
HN
HN
N
N
COOH
Histidine
Histamine
NH 2
N
N
τ-Methylhistamine
SCHEME 17.1 Synthesis and metabolism of histamine. HDC, histidine decarboxylase; DAO, diamine oxidase;
HMT, histamine N -methyltransferase.
Some of the symptoms of allergic conditions in the skin and the airway system are known to
result from histamine release after mast cell degranulation. In 1937, Bovet and Staub discovered the
i rst compounds that antagonize these effects of histamine. From henceforth, there has been intense
research devoted toward i nding novel ligands with (anti)histaminergic activity.
As more (patho) physiological processes that are mediated by histamine (e.g., stomach acid
secretion and neurotransmitter release) were studied, it became apparent that the action of hista-
mine is mediated by several subtype receptors. This resulted in the identii cation of the histamine
H 2 receptor in 1966, the histamine H 3 receptor in 1983, and the histamine H 4 receptor in 2000 (note
the interval of 17 years). The i rst three histamine receptor subtypes were discovered by classi-
cal pharmacological means, i.e., using subtype selective ligands that were developed by medicinal
chemists. The histamine H 4 receptor was discovered using the human genome, nicely illustrating
the impact of molecular biology and genomics in drug discovery.
In this chapter we will describe in detail the state-of-the-art knowledge on the molecular features
of the histamine receptor proteins, the medicinal chemistry of the four histamine receptors, and the
(potential) therapeutic applications of selective receptor ligands.
17.2 THE HISTAMINE H 1 RECEPTOR: MOLECULAR ASPECTS
AND SELECTIVE LIGANDS
17.2.1 M OLECULAR A SPECTS OF THE H ISTAMINE H 1 R ECEPTOR P ROTEIN
The H 1 receptor belongs to the large family of rhodopsin-like, G-protein coupled receptors (GPCRs).
In 1991, the cDNA encoding a bovine H 1 receptor protein was cloned after an expression cloning strat-
egy in Xenopus oocytes by Fukui and coworkers. The human H 1 receptor gene resides on chromosome
three and the deduced amino acid sequence revealed a 491 amino acid protein of 56 kDa. Using the
cDNA sequence encoding the bovine H 1 receptor, the cDNA sequences and intronless genes encoding
the rat, guinea pig, human, and mouse H 1 receptor proteins were cloned soon thereafter. These recep-
tor proteins are slightly different in length, highly homologous, and do not show major pharmacologi-
cal differences. The stimulation of the H 1 receptor leads to the phospholipase C-catalyzed formation
of the second messengers inositol 1,4,5-triphosphate (IP 3 ) and 1,2-diacylglycerol (DAG), which in turn
lead to the mobilization of intracellular calcium and the activation of protein kinase C, respectively.
17.2.2 H 1 R ECEPTOR A GONISTS
The modii cation of the imidazole moiety of histamine has been the most successful approach for
obtaining selective H 1 agonists (Figure 17.1). The presence of the tautomeric N π - N τ system of the
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