Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1998-01-05
2000-01-18
Kemmerer, Elizabeth
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 231, 536 245, 435 691, 4353201, 435325, 4352523, C07H 2104, C12N 1512, C12N 1563
Patent
active
060158883
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to the detection of variations in human histamine H.sub.2 receptors, and more particularly to the development of new compounds useful in the sequencing and identification of a human histamine H.sub.2 receptor and their use in the diagnosis and treatment of certain human disorders, for example, brain disorders. The invention also relates to new compounds and a method for detecting an allelic polymorphic variation within the human population for the gene encoding the histamine H.sub.2 receptor and their use in the diagnosis and treatment of human disorders.
BACKGROUND ART
The human H.sub.2 receptor was first identified by Black et al Nature (1972), 236, 385-390. This was followed by the demonstration of the receptor in the mammalian brain by Baudry et al (1975) Nature 253, 362-363, and Haas and Bucher (1975) Nature 255, 634-635. Gantz et al (1991) Biochem. Biophys. Res. Comm. 178,3, 1386-1392 have recently identified the sequence of a human H.sub.2 receptor cDNA from gastric parietal cells by using the polymerase chain reaction (PCR) and degenerated oligonucleotide primers whose sequence was obtained from the canine H.sub.2 receptor previously cloned by this group, Gantz et al (1991) Proc. Nat. Acad. Sci. USA 88, 429-433. This sequence was characterised as an intronless gene encoding a typical seven transmembrane domain aminergic receptor protein.
The receptor is coupled to heterotrimeric GTPases (G proteins), but differs from other monoamine receptors in this G protein coupled superfamily in several respects. The human gastric H.sub.2 receptor is shorter than most other receptors in this class (359 amino acids) and lacks the two serine residues in the fifth transmembrane region (TM5). There exists instead an aspartate and a threonine residue, so far unique in this region. These two residues may be important for binding with the nitrogen atoms of the imidazole ring of histamine as suggested by Birdsall (1991) Trends in Pharmacological Sci. Jan, 12, 9-10.
Histamine is a natural constituent of many organs and tissues including the gastrointestinal tract, the immune system and the brain, Green et al (1987) Agents and Actions 22, 1-15. It is a central neurotransmitter in the brain and is formed in the posterior hypothalamus from exogenous histidine by histidine decarboxylase (HDC). It is subsequently metabolised by histamine methyltransferase (HMT), Prell et al (1986) Ann. Rev. Neurosci. 9, 209-254. The cell bodies and neuronal pathways for histamine have been mapped in the human brain using immunocytochemistry by Panula et al (1990) Neuroscience 34, 127-132. Its cells project from the tuberomamillary nucleus of the posterior hypothalamus to almost every region of the brain. There are three known histamine receptors; H.sub.1, H.sub.2 and H.sub.3, the latter functioning as an autoreceptor. The H.sub.2 receptor specifically has been localised in the human brain by Traiffort et al (1992) J. of Neurochem. 59, 1, 290-299. using receptor autoradiography.
Histamine is known to have significant effects in the central nervous system (CNS). It has been implicated in the CNS mediated mechanisms of arousal ever since the sedating effect of H.sub.1 receptor antagonists (eg,. chlorpheniramine, chloropromazine) had been noticed clinically. The use of H.sub.2 receptor antagonists in the human brain however, has shown, that these compounds, unlike those acting on the H.sub.1 receptor, do not produce any effect on psychomotor functioning, or a subjective feeling of sedation or arousal in healthy subjects, White et al (1988) Psychopharmacology 95, 1-14. Some H.sub.2 receptor antagonists (eg. cimetidine) are known to cause confusion in elderly or severely medically ill patients, perhaps in part due to a co-existing anti-cholinergic effect. H.sub.1 and H.sub.2 receptor antagonists in large doses have been reported to cause hallucinations, Csillag et al (1973) Med. J. Aust. 1, 653-654, Argawal (1978) J. Am. Med. Assoc. 240, 214. Animal studies have shown that histamine applied directly to th
REFERENCES:
Gantz, et al. "Molecular Cloning of the Human Histamine H2 Receptor" Biochemical and Biophysical Research Communications vol. 178, No. 3, 1991. pp. 1386-1392.
Gantz, et al. "Molecular Basis for the Interaction of Histamine with the Histamine H2 Receptor" The Journal of Biological Chemistry 1992 vol. 267 No. 29, Issue of Oct. 15, pp. 10840-10843.
Nishi, et al. "Identification of the Promoter Region of The Human Histamine H.sub.2 -Receptor Gene" Biochemical and Biophysical vol. 320 1995 pp. 1096-1101.
Ohta, et al. "Site-Directed Mutagenesis of the Histamine H.sub.1 Receptor: Roles Of Aspartic Acid.sup.107, Asparagine.sup.194 and Threonine.sup.198 " vol. 203, No. 2.1994.
Orange, et al. "Allelic variation of the human histamine H.sub.2 receptor gene is a major predisposing factor for schizophrenia".
Orange, et al. "Individuals with schizophrenia have an increased incidence of the H.sub.2 R.sub.649G allele for the histamine H.sub.2 receptor gene" Molecular Phychiatry 1996 466-469.
Orange, et al. "Allelic Variations of the human histamine H.sub.2 receptor gene", Molecular Neuroscience, NeuroReport 7:1293-1296 (1996).
Lin et al. Diffrential Fluorescent Staining of Human Chromosomes with Daunomycin and Adriamycin--The D-Bands Science, vol. 190, pp. 61-63, 1975.
Heath Paul Roy
Orange Paul Richard
Pearson Ronald Carl Alan
Wright Simon Ralph
Basi Nirmal S.
Kemmerer Elizabeth
University of Sheffield
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