Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Patent
1995-05-10
2000-10-10
Spector, Lorraine
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
536 235, 536 231, 530350, 4353201, C12N 1512, C07K 14705
Patent
active
061300586
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention concerns a cell line, and in particular relates to a stable cell line capable of expressing human or animal N-methyl-D-aspartate (NMDA) receptors. The invention also relates to complementary DNAs (cDNAs) encoding novel human NMDA receptor subunits, and concerns in particular the nucleotide and deduced amino acid sequences of the human NMDA R2A receptor subunit, and of various isoforms of the human NMDA R1 receptor subunit.
BACKGROUND
The NMDA receptor is the major excitatory amino acid receptor that mediates glutamate transmission in the central nervous system. This receptor has been implicated in neuronal modulation, including long term potentiation in the hippocampus (Collingridge and Singer, TIPS, 1990, 11, 290). It is consequently believed to play a key role in memory acquisition and learning.
The integral channel of the NMDA receptor allows ca.sup.2+ to permeate as well as Na.sup.+ and K.sup.+, and presents at least seven pharmacologically distinct sites. These include a glutamate binding site, a glycine binding site, a polyamine site, a dizocilpine binding site, a voltage dependent Mg.sup.2+ site, a Zn.sup.2+ binding site (Wong and Kemp, Ann. Rev. Pharmacol. Toxicol., 1991, 31, 401) and an ifenprodil binding site (Carter et al., J. Pharmacol. Exy. Ther., 1988, 247, 1222).
The development of potent and selective NMDA receptor antagonists which penetrate into the brain has received considerable attention of late as an attractive strategy for treating and/or preventing conditions which are believed to arise from over-stimulation of neurotransmitter release by excitatory amino acids. Such conditions notably include neurodegenerative disorders arising as a consequence of such pathological conditions as stroke, hypoglycaemia, cerebral palsy, transient cerebral ischaemic attack, cerebral ischaemia during cardiac pulmonary surgery or cardiac arrest, perinatal asphyxia, epilepsy, Huntington's chorea, Alzheimer's disease, Amyotrophic Lateral Sclerosis, Parkinson's disease, Olivo-ponto-cerebellar atrophy, anoxia such as from drowning, spinal cord and head injury, and poisoning by exogenous and endogenous NMDA receptor agonists and neurotoxins, including environmental neurotoxins.
NMDA receptor antagonists may also be useful as anticonvulsant and antiemetic agents, as well as being of value in the prevention or reduction of dependence on dependence-inducing agents such as narcotics.
NMDA receptor antagonists have recently been shown to possess analgesic (see, for example, Dickenson and Aydar, Neuroscience Lett., 1991, 121, 263; Murray et al., Pain, 1991, 44, 179; and Woolf and Thompson, Pain, 1991, 44, 293) and anxiolytic (see, for example, U.S. Pat. No. 5,145,866; and Kehne et al., Eur. J. Pharmacol., 1991, 193, 283) effects, and such compounds may accordingly be useful in the management of pain, depression and anxiety.
Compounds possessing functional antagonist properties for the NMDA receptor complex are stated in WO-A-91/19493 to be effective in the treatment of mood disorders, including major depression, bipolar disorder, dysthymia and seasonal affective disorder (cf. also Trullas and Skolnick, Eur. J. Pharmacol., 1990, 185, 1). Such compounds may consequently be of benefit in the treatment and/or prevention of those disorders.
The association of NMDA receptor antagonists with regulation of the dopaminergic system has recently been reported (see, for example, Werling et al., J. Pharmacol. Exp. Ther., 1990, 255, 40; Graham et al., Life Sciences, 1990, 47, PL-41; Hutson et al., Br. J. Pharmacol., 1991, 103, 2037; and Turski et al., Nature (London), 1991, 349, 414). This suggests that such compounds may thus be of assistance in the prevention and/or treatment of disorders of the dopaminergic system such as schizophrenia and Parkinson's disease.
It has also been reported recently (see Lauritzen et al., Journal of Cerebral Blood Flow and Metabolism, 1991, vol. 11, suppl. 2, Abstract XV-4) that NMDA receptor antagonists block cortical spreading depression (CSD), wh
REFERENCES:
Monyer, et al., "Heteromeric NMDA receptors: molecular and functional distinction of subtypes", Science, vol. 256, May 22, 1992, pp. 1217-1221.
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le Bourdelles Beatrice
Myers Janice Ann
Whiting Paul John
Kaufman Claire M.
Merck Sharpe & Dohme Ltd.
Spector Lorraine
Tribble Jack L.
Yablonsky Michael D.
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