Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-04-12
2004-03-02
Rotman, Alan L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S254020, C514S326000, C514S370000, C544S133000, C544S137000, C544S369000, C546S209000, C548S190000
Reexamination Certificate
active
06699866
ABSTRACT:
BACKGROUND OF THE INVENTION
Dopamine is a neurotransmitter found in various parts of the central nervous system. It is most prevalent in the substantia nigra (A9), the neostriatum, and the ventral tegmental area (A10). Dopamine binds to two general classes of receptors, termed D1- and D2-like receptors. These receptors are differentiated pharmacologically, biologically, physiologically, and in anatomical distribution. Furthermore, the D1-like receptor class consists of several subtypes, D
1
and D
5
. Likewise, the D2-like receptor class also consists of several subtypes, D
2
, D
3
, and D
4
. All of the subtypes of dopamine receptors are coupling to and activate different G protein complexes. The D1-like receptors interact with the Gs complex to activate adenylyl cyclase, whereas the D2-like receptors interact with Gi to inhibit cAMP production.
The D
3
receptor subtype is found only in the CNS. It is found in greater abundance in the limbic regions of the brain, such as the nucleus accumbens. These regions receive dopamine input from the ventral tegmental area and are known to be associated with cognitive, emotional, and endocrine functions. It is relatively absent in the nigrostriatal system, suggesting that the D
3
receptor may more likely be involved in the etiology of psychotic diseases, instead of locomotor abnormalities.
Many clinically efficacious antipsychotic agents, such as eticlopride, haloperidol, and olanzapine, bind to the D
3
receptor. However, most of these compounds also bind to the D
2
receptor, in addition to a host of other receptors and ion channels. High affinity of ligands for the D
2
receptor in the striatum is believed to be the cause of serious extrapyramidal side-effects that can result in termination of therapy. In addition, this also has made elucidating the role of D
3
more difficult.
Dopamine plays a major role in addiction, depression and psychosis. Many of the concepts that apply to dopamine apply to other neurotransmitters as well. As a chemical messenger, dopamine is similar to adrenaline. Dopamine affects brain processes that control movement, emotional response, and ability to experience pleasure and pain. Regulation of dopamine plays a crucial role in our mental and physical health. Neurons containing the neurotransmitter dopamine are clustered in the midbrain in an area called the substantia nigra. In Parkinson's disease, the dopamine-transmitting neurons in this area die. As a result, the brains of people with Parkinson's disease contain almost no dopamine. To help relieve their symptoms, these patients are given L-DOPA, a drug that can be converted in the brain to dopamine.
Certain drugs are known as dopamine agonists. These drugs bind to dopamine receptors in place of dopamine and directly stimulate those receptors. Some dopamine agonists are currently used to treat Parkinson's disease. These drugs can stimulate dopamine receptors even in someone without dopamine-secreting neurons. In contrast to dopamine agonists, dopamine antagonists are drugs that bind but don't stimulate dopamine receptors. Antagonists can prevent or reverse the actions of dopamine by keeping dopamine from attaching to receptors.
Dopamine antagonists are traditionally used to treat schizophrenia and related mental disorders. A person with schizophrenia may have an overactive dopamine system. Dopamine antagonists can help regulate this system by “turning down” dopamine activity.
Cocaine and other drugs of abuse can alter dopamine function. Such drugs may have very different actions. The specific action depends on which dopamine receptors the drugs stimulate or block, and how well they mimic dopamine. Drugs such as cocaine and amphetamine produce their effects by changing the flow of neurotransmitters. These drugs are defined as indirect acting because they depend on the activity of neurons. In contrast, some drugs bypass neurotransmitters altogether and act directly on receptors. Such drugs are direct acting.
Muscarinic acetylcholine receptors constitute a group of five receptor subtypes (M
1
-M
5
) that mediate cellular responses by activating heterotrimeric G proteins. These receptors are abundantly expressed throughout the central and peripheral nervous systems and play an important role in numerous physiological processes. Some of these include learning and memory, adjusting the amount of light that impinges on the retina, and regulating various organs innervated by autonomic nerves (e.g., gastrointestinal tract, heart, trachea and exocrine glands). In recent years, the signaling pathways of G protein-linked receptors have been worked out in great detail.
In the late 1980s, molecular cloning techniques identified the aforementioned five subtypes of muscarinic receptors. Each receptor shares common features including specificity of binding for the agonists acetylcholine and carbamylcholine and the classical antagonists atropine and quinuclidinyl benzilate. Each receptor subtype couples to a second messenger system through an intervening G-protein. M
1
, M
3
and M
5
receptors stimulate phosphoinositide metabolism while M
2
and M
4
receptors inhibit adenylate cyclase. The tissue distribution differs for each subtype. M
1
receptors are found in the forebrain, especially in the hippocampus and cerebral cortex. M
2
receptors are found in the heart and brainstem while M
3
receptors are found in smooth muscle, exocrine glands and the cerebral cortex. M
4
receptors are found in the neostriatum and M
5
receptor mRNA is found in the substantia nigra, suggesting that M
5
receptors may regulate dopamine release at terminals within the striatum. The structural requirements for activation of each subtype remain to be elucidated.
Acetylcholine and carbamylcholine bind to muscarinic receptors. Muscarinic responses to these ligands may produce excitation or inhibition and involve second messenger systems, as opposed to the direct opening of an ion channel. Muscarinic receptors are G protein-coupled receptors and mediate their responses by activating a cascade of intracellular pathways. Muscarine is the prototypical muscarinic agonist and derives from the fly agaric mushroom
Amanita muscaria
. Like acetylcholine, muscarine contains a quaternary nitrogen important for action at the anionic site of the receptor (an aspartate residue in transmembrane domain III).
The muscarinic antagonists scopolamine and atropine are derived from natural sources. They are both alkaloids (natural, nitrogenous organic bases, usually containing tertiary amines) from the nightshade plant
Atropa belladonna
. The potent anticholinergics are used to control the secretion of saliva and gastric acid, slow gut motility, and prevent vomiting. They also have a limited therapeutic use for the treatment of Parkinson's disease. In large doses however, the muscarinic antagonists with tertiary amines have severe central effects, including hallucinations and memory disturbances. In recent years, the quaternary muscarinic antagonist ipratroprium has been used in the treatment of chronically obstructed pulmonary disorder as an adjunct to &bgr;
2
agonist therapy. M
3
muscarinic receptors mediate bronchoconstriction in the airways. Muscarinic antagonists such as ipratropium and the long-lasting tiotropium are effective bronchodilators. Centrally active muscarinic receptor agonists show promise for the treatment of Alzheimer's disease. The rationale for therapy involves replacement of acetylcholine, which is depleted in Alzheimer's patients as the basal forebrain neurons degenerate. Muscarinic receptor agonists also show promise for treatment of peptic ulcers, pulmonary obstruction disorders, asthma, and urinary incontinence. An ideal candidate for a drug would have several features including high CNS penetration, high efficacy and selectivity for forebrain receptors and a low incidence of side effects.
Serotonin (5-hydroxytryptamine, 5-HT) is widely distributed in animals and plants, occurring in vertebrates, fruits, nuts, and venoms. A number of congeners of sero
Cuny Gregory D.
Hauske James R.
Heffernan Michele L. R.
Holland Joanne M.
Persons Paul E.
Foley & Hoag LLP
Gordon Dana M.
Rotman Alan L.
Sepracor Inc.
Shiao Roei
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