Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1999-09-14
2001-06-26
Duffy, Patricia A. (Department: 1645)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S070100, C435S325000, C435S252300, C435S254110, C436S501000, C436S804000, C530S350000
Reexamination Certificate
active
06251617
ABSTRACT:
This application is related to the following co-pending applications: “Glycine Transporter-Transfected Cells and Uses Thereof,”, Ser. No. 08/655,836, filed May 31, 1996; “Pharmaceutical For Treatment Of Neurological And Neuropsychiatric Disorders,” Ser. No. 08/656,063, filed May 31, 1996, and a Continuation-in-Part thereof, Ser. No. 08/808,754, filed Feb. 27, 1997; “Pharmaceutical For Treatment of Neuropsychiatric Disorders,” and a Continuation-in-Part thereof, Ser. No. 08/808,755 filed Feb. 27, 1997, Ser. No. 08/655,912, filed May 31, 1996; “Pharmaceutical For Treating Of Neurological and Neuropsychiatric Disorders,” Ser. No. 08/655,847, filed May 31, 1996, and a Continuation-in-Part thereof, Ser. No. 08/807,681, filed Feb. 27, 1997; and “Human Glycine Transporter,” Attorney Docket No. 317743-108 Ser. No. 08/700,013, filed Aug. 20, 1996.
The present invention relates to nucleic acid encoding a “GlyT1d” member of the family of glycine transports, to the isolated protein encoded by the nucleic acid, and to the field of drug discovery.
Synaptic transmission is a complex for of intercellular communication that involves a considerable array of specialized structures in both the pre- and post-synaptic neuron. High-affinity neurotransmitter transports are one such component, located on the pre-synaptic terminal and surrounding glial cells (Kanner and Schuldiner,
CRC Critical Reviews in Biochemistry
22: 1032, 1987). Transporters sequester neurotransmitter from the synapse, thereby regulating the concentration of neurotransmitter in the synapse, as well as its duration in the synapse therein, which together influence the magnitude of synaptic transmission. Further, by preventing the spread of transmitter to neighboring synapses, transporters maintain the fidelity of synaptic transmission. Last, by sequestering released transmitter into the presynaptic terminal, transports allow for transmitter reutilization.
Neurotransmitter transport is dependent on extracellular sodium and the voltage difference across the membrane; under conditions of intense firing, as, for example, during a seizure, transporters can function in reverse, releasing neurotransmitter in a calcium-independent non-exocytotic manner (Attwell et al.,
Neuron
11: 401-407, 1993). Pharmacologic modulation of neurotransmitter transports thus provides a means for modifying synaptic activity, which provides useful therapy for the treatment of neurological and psychiatric disturbances.
The amino acid glycine is a major neurotransmitter in the mammalian nervous system, functioning at both inhibitory and excitatory synapses. By nervous system, both the central and peripheral portions of the nervous system are intended. These distinct functions of glycine are mediated by two different types of receptor, each of which is associated with a different class of glycine transporter. The inhibitory actions of glycine are mediated by glycine receptors that are sensitive to the convulsant alkaloid, strychnine, and are thus referred to as “strychnine-sensitive.” Such receptors contain an intrinsic chloride channel that is opened upon binding of glycine to the receptor; by increasing chloride conductance, the threshold for firing of an action potential is increased. Strychnine-sensitive glycine receptors are found predominantly in the spinal cord and brainstem, and pharmacological agents that enhance the activation of such receptors will thus increase inhibitory neurotransmission in these regions.
Glycine functions in excitatory transmission by modulating the actions of glutamate, the major excitatory neurotransmitter in the central nervous system. See Johnson and Ascher,
Nature
325
:
529
-
531
,
1987
; Fletcher et al.,
Glycine Transmission
, (Otterson and Storm-Mathisen, eds., 1990), pp. 193-219. Specifically, glycine is an obligatory co-agonist at the class of glutamate receptor termed N-methyl-D-aspartate (NMDA) receptor. Activation of NMDA receptors increases sodium and calcium conductance, which depolarizes the neuron, thereby increasing the likelihood that the neuron will fire an action potential. NMDA receptors are widely distributed throughout the brain, with a particularly high density in the cerebral cortex and hippocampal formation.
Molecular cloning has revealed the existence in mammalian brains of two classes of glycine transporters, termed GlyT1 and GlyT2. GlyT1 is found predominantly in the forebrain, and its distribution corresponds to that of glutamatergic pathways and NMDA receptors (Smith, et al.,
Neuron
8:927-935, 1992). Molecular cloning has further revealed the existence of three variants of GlyT-1, termed GlyT-1a, GlyT-1b and GlyT-1c (Kim et al.,
Molecular Pharmacology
45: 608-617, 1994), each of which displays a unique distribution in the brain and peripheral tissues. GlyT2, in contrast, is found predominantly in the brain stem and spinal cord, and its distribution corresponds closely to that of strychnine-sensitive glycine receptors (Liu et al.,
J. Biol. Chem.
268: 22802-22808, 1993; Jursky and Nelson,
J. Neurochem.
64: 1026-1033, 1995. These observations are consistent with the view that, by regulating the synaptic levels of glycine, GlyT1 and GlyT2 selectively influence the activity of NMDA receptors and strychnine-sensitive glycine receptors, respectively.
Sequence comparisons of GlyT1 and GlyT2 have revealed that these glycine transporters are members of broader family of sodium-dependent neurotransmitter transporters, including, for example, transporters specific for gamma-amino-n-butyric acid (GABA) and others. Uhl,
Trends in Neuroscience
15: 265-268, 1992: Clark and Amara,
BioEssays
15: 323-332, 1993. Overall, each of these transporters includes 12 putative transmembrane domains that predominantly contain hydrophobic amino acids.
Compounds that inhibit or activate glycine transporters would be expected to alter receptor function, and provide therapeutic benefits in a variety of disease states. For example, inhibition of GlyT2 can be used to diminish the activity of neurons having strychnine-sensitive glycine receptors via increasing synaptic levels of glycine, thus diminishing the transmission of pain-related (i.e., nociceptive) information in the spinal cord, which has been shown to be mediated by these receptors. Yaksh, Pain, 111-123 (1989). Additionally, enhancing inhibitory glycinergic transmission through strychnine-sensitive glycine receptors in the spinal cord can be used to decrease muscle hyperactivity, which is useful in treating diseases or conditions associated with increased muscle contraction, such as spasticity, myoclonus, and epilepsy (Truong et al.,
Movement Disorders,
3, 77-87 (1988); Becker,
FASEB J.,
4, 2767-2774 (1990)). Spasticity that can be treated via modulation of glycine receptors is associated with epilepsy, stroke, head trauma, multiple sclerosis, spinal cord injury, dystonia, and other conditions of illness and injury of the nervous system.
NMDA receptors are critically involved in memory and learning (Rison and Stanton,
Neurosci. Biobehav. Rev.,
19, 533-552 (1995); Danysz et al.,
Behavioral Pharmacol.,
6, 455-474 (1995)); and, furthermore, decreased function of NMDA-mediated neurotransmission appears to underlie, or contribute to, the symptoms of schizophrenia (Olney and Farber,
Archives General Psychiatry
52: 998-1007 (1996)). Thus, agents that inhibit Gly-T1 and thereby increase glycine activation of NMDA receptors can be used as novel antipsychotics and anti-dementia agents, and to treat other diseases in which cognitive processes are impaired, such as attention deficit disorders and organic brain syndromes. Conversely, over-activation of NMDA receptors has been implicated in a number of disease states, in particular the neuronal death associated with stroke and possibly neurodegenerative diseases, such as Alzheimer's disease, multi-infarct dementia, AIDS dementia, Parkinsons's disease, Huntington's disease, amyotrophic lateral sclerosis or other conditions in which neuronal cell death occurs, such as stroke and head trauma. Coyle
Albert Vivian R.
Kowalski Leslie R. Z.
Allelix Neuroscience Inc.
Dechert
Duffy Patricia A.
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