Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1996-06-07
2001-04-03
Ulm, John (Department: 1646)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C435S069100, C435S252300, C435S320100
Reexamination Certificate
active
06211353
ABSTRACT:
BACKGROUND OF THE INVENTION
In the mammalian central nervous system (CNS), the transmission of nerve impulses is controlled by the interaction between a neurotransmitter, that is released by a sending neuron, and a surface receptor on a receiving neuron, which causes excitation of this receiving neuron. L-Glutamate, which is the most abundant neurotransmitter in the CNS, mediates the major excitatory pathway in mammals, and is referred to as an excitatory amino acid (EAA). The receptors that respond to glutamate are called excitatory amino acid receptors (EAA receptors). See Watkins & Evans,
Annual Reviews in Pharmacology and Toxicology
, 21:165 (1981); Monaghan, Bridges, and Cotman,
Annual Reviews in Pharmacology and Toxicology
, 29:365 (1989); Watkins, Krogsgaard-Larsen, and Honore,
Transactions in Pharmaceutical Science
, 11:25 (1990). The excitatory amino acids are of great physiological importance, playing a role in a variety of physiological processes, such as long-term potentiation (learning and memory), the development of synaptic plasticity, motor control, respiration, cardiovascular regulation, and sensory perception.
Excitatory amino acid receptors are classified into two general types. Receptors that are directly coupled to the opening of cation channels in the cell membrane of the neurons are termed “ionotropic.” This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonists N-methyl-D-aspartate (NMDA), &agr;-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainic acid (KA).
The second general type of receptor is the G-protein or second messenger-linked “metabotropic” excitatory amino acid receptor. This second type is coupled to multiple second messenger systems that lead to enhanced phosphoinositide hydrolysis, activation of phospholipase D, increases or decreases in cAMP formation, and changes in ion channel function. Schoepp and Conn,
Trends in Pharmacological Science
, 14:13 (1993). Both types of receptors appear not only to mediate normal synaptic transmission along excitatory pathways, but also participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and Sladeczek,
Trends in Pharmacological Science
, 11:508 (1990); McDonald and Johnson,
Brain Research Reviews
, 15:41 (1990).
The excessive or inappropriate stimulation of excitatory amino acid receptors leads to neuronal cell damage or loss by way of a mechanism known as excitotoxicity. This process has been suggested to mediate neuronal degeneration in a variety of conditions. The medical consequences of such neuronal degeneration makes the abatement of these degenerative neurological processes an important therapeutic goal.
The metabotropic glutamate receptors are a highly heterogeneous family of glutamate receptors that are linked to multiple second-messenger pathways. These receptors function to modulate the presynaptic release of glutamate, and the postsynaptic sensitivity of the neuronal cell to glutamate excitation. Agonists and antagonists of these receptors may be useful for the treatment of acute and chronic neurodegenerative conditions, and as antipsychotic, anticonvulsant, analgesic, anxiolytic, antidepressant, and anti-emetic agents.
The present invention provides an additional human excitatory amino acid receptor, designated mGluR5, to those previously known. The characterization and treatment of physiological disorders is hereby furthered.
SUMMARY OF THE INVENTION
This invention provides an isolated amino acid compound useful as a human metabotropic glutamate receptor, said compound comprising the amino acid sequence
Met Val Leu Leu Leu Ile Leu Ser Val Leu Leu Leu Lys Glu Asp Val
1 5 10 15
Arg Gly Ser Ala Gln Ser Ser Glu Arg Arg Val Val Ala His Met Pro
20 25 30
Gly Asp Ile Ile Ile Gly Ala Leu Phe Ser Val His His Gln Pro Thr
35 40 45
Val Asp Lys Val His Glu Arg Lys Cys Gly Ala Val Arg Glu Gln Tyr
50 55 60
Gly Ile Gln Arg Val Glu Ala Met Leu His Thr Leu Glu Arg Ile Asn
65 70 75 80
Ser Asp Pro Thr Leu Leu Pro Asn Ile Thr Leu Gly Cys Glu Ile Arg
85 90 95
Asp Ser Cys Trp His Ser Ala Val Ala Leu Glu Gln Ser Ile Glu Phe
100 105 110
Ile Arg Asp Ser Leu Ile Ser Ser Glu Glu Glu Glu Gly Leu Val Arg
115 120 125
Cys Val Asp Gly Ser Ser Ser Ser Phe Arg Ser Lys Lys Pro Ile Val
130 135 140
Gly Val Ile Gly Pro Gly Ser Ser Ser Val Ala Ile Gln Val Gln Asn
145 150 155 160
Leu Leu Gln Leu Phe Asn Ile Pro Gln Ile Ala Tyr Ser Ala ‘Ihr Ser
165 170 175
Met Asp Leu Ser Asp Lys Thr Leu Phe Lys Tyr Phe Met Arg Val Val
180 185 190
Pro Ser Asp Ala Gln Gln Ala Arg Ala Met Val Asp Ile Val Lys Arg
&ems
Burnett, Jr. James Paul
Mayne Nancy Gail
Sharp Robert Leon
Snyder Yvonne Marie
Eli Lilly and Company
Ulm John
Wilson Alexander
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