Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-09-27
2002-05-21
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S217000, C514S220000, C514S249000, C514S285000, C514S317000, C514S318000, C514S428000, C514S646000
Reexamination Certificate
active
06391871
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to neurology and pharmacology, and more specifically to drug treatments that can prevent or reduce the brain damage caused by Alzheimer's disease.
The following Background sections provide introductory information on (1) neurotransmitter receptors in the brain; (2) mechanisms by which these transmitter and receptor systems may contribute to neuronal degeneration in Alzheimer's disease; and (3) certain types of drugs that can be used to prevent or reduce neuronal degeneration in patients suffering from Alzheimer's disease.
The following Background sections are not strictly limited to prior art. The extremely complex (and apparently contradictory and paradoxical) neurological systems and processes involved in Alzheimer's disease have stubbornly confounded the efforts of literally thousands of highly skilled researchers and physicians, for decades. Accordingly, the following narrative is an effort to explain, as clearly and logically as possible, what is happening inside the brain of someone suffering from Alzheimer's disease, and how various neurological networks interact with each other in apparently paradoxical ways. Substantial parts of this explanation come from the Applicants' recent research discoveries. Because some of these recent discoveries involve neurological processes that occur naturally, inside the brain, they are discussed in the Background narrative. However, these recent discoveries by the Applicants should not be regarded as prior art.
Glutamate (GLU) and Neuronal Glutamate Receptors
Glutamate (sometimes abbreviated as GLU) is one of the 20 common amino acids used by all living cells to make protein. Glutamate is the ionized form of glutamic acid; the ionized form is the predominant form in neutral solutions, at pH 7.
In addition to its role as a building block for proteins, glutamate plays an entirely different and crucial role in the central nervous system (CNS) of higher animals, including mammals and birds. Although much of the discussion that follows is equally true for the spinal cord, which is part of the CNS, this discussion focuses on the brain, since that is where the damage and degeneration occurs in patients suffering from Alzheimer's disease.
Within the brain, glutamate serves as the predominant excitatory transmitter molecule which carries signals between nerve cells (e.g., Olney 1987; full citations to books and articles are provided below). In a brief overview, this process can be summarized as follows. At a neuronal synapse (i.e., a signal-transmitting junction between two nerve cells), a molecule of glutamate is released by the signal-transmitting neuron. The glutamate molecule enters the fluid in the gap between the two neurons, and it rapidly contacts the exposed portion of a “glutamate receptor” on the surface of the signal-receiving neuron.
As used herein, “receptor” refers to a macromolecular binding site (usually a protein, which may also be glycosylated or phosphorylated) which is at least partially exposed on the surface of a cell, and which has specific and limited affinity for one or more fluid-borne molecules, called “ligands” (these usually are neurotransmitters or hormones). When a ligand contacts an appropriate receptor, a brief binding reaction occurs which causes a cellular response, such as opening of an ion channel, which leads to activation and depolarization of the neuron. Most receptor molecules are proteins which straddle the membrane of a cell, with an external portion for binding reactions, and an internal portion which helps carry out the cellular response that occurs when the receptor is activated by a ligand.
This is not a rigid definition, and different scientists sometimes use the term “receptor” inconsistently. For example, they may either include or exclude various additional components, such as an ion channel which is opened or closed by a receptor. All of the glutamate receptors relevant to the present invention are associated with ion channels, and therefore are referred to as “ionotropic” receptors.
In pharmacological terminology, an “agonist” is a molecule which activates a certain type of receptor. For example, glutamate molecules (and certain drugs such as NMDA, as described below) act as agonists when they excite EAA receptors. By contrast, an “antagonist” is a molecule which prevents or reduces the effects exerted by an agonist at a receptor.
Upon being activated (“excited”) by a glutamate molecule, a glutamate receptor protein changes its conformation, in a manner which briefly opens an ion channel that serves as a conduit through the cell membrane. Calcium (Ca
++
), sodium (Na
+
), and certain other types of ions rapidly flow through the ion channel when it is briefly opened, thereby altering several ionic gradients that normally exist across the membranes of neurons at rest. This activates (stimulates) a neuron, causing it to release its own neurotransmitters at other (“downstream”) synapses, thereby transmitting signals to still other neurons.
To reset the mechanism and get the transmitting and receiving neurons back to a resting/ready condition, where both neurons are ready to handle another nerve signal, the ion channel quickly closes, and the glutamate receptor protein on the signal-receiving neuron releases the glutamate molecule. The glutamate molecule floats back into the synaptic fluid between the neurons, and a molecular transport system quickly intercepts it and transports it back inside the transmitting neuron. The signal-receiving neuron activates a set of molecular pumps, which rapidly transport calcium and sodium ions (which had entered the cell though the glutamate-controlled ion channel) back out of the neuron to regain a “polarized” condition, so that it will be ready to receive another nerve signal.
This entire set of chemical actions—release of glutamate by a transmitting neuron, activation and depolarization of a signal-receiving neuron, release of the glutamate transmitter molecule by the receptor protein, clearance of the free glutamate from the synaptic fluid, and restoration of the polarized/ready state in the signal-receiving neuron—is extraordinarily rapid. All of these steps, together, occur within a few milliseconds.
Since glutamate is an amino acid that can function as an excitatory neurotransmitter inside the brain, it is often called an “excitatory amino acid” (EAA). Another type of amino acid, aspartate (the ionized form of aspartic acid), can also function as an excitatory amino acid in the brain; therefore, glutamate receptors are sometimes referred to as “EAA” receptors, since they can be triggered by either of two amino acids (glutamate or aspartate). However, glutamate is used much more widely than aspartate as a neurotransmitter, and “EAA receptors” are referred to herein (and by most scientists) as glutamate or GLU receptors.
Types of GLU Receptors: NMDA and non-NMDA Receptors
There are three distinct types of ionotropic glutamate receptors in the mammalian central nervous system (as well as a “metabotropic” glutamate receptor, which is not of interest herein). Although all three GLU receptor types are normally triggered by exactly the same EAA neurotransmitters in the CNS (i.e., glutamate or aspartate molecules), these three different subtypes of glutamate receptors have been found by researchers to have different binding properties, when certain types of artificial drugs are used as probes to study neuronal activity.
One major class of GLU receptors is referred to as NMDA receptors, since they bind preferentially to NMDA, which is n-methyl-D-aspartate. This analog of aspartic acid normally does not occur in nature, and is not present in the brain; it is, however, a useful probe drug which is widely used by neurologists to study and differentiate the roles of NMDA and non-NMDA receptors. When molecules of NMDA contact neurons having NMDA receptors, the NMDA strongly activates NMDA receptors, and acts as a glutamate agonist, causing the same type of neuro
Farber Nuri B.
Olney John W.
Jagoe Donna
Kelly Patrick D.
Krass Frederick
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