Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-03-25
1999-11-23
Tsang, Cecilia J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514213, 514295, 514411, 514430, 514431, 514437, 514438, 514443, 514454, 514450, 514451, 514455, 514461, 514468, 548400, 548434, 540576, 540581, 546 97, 549 12, 549 26, 549 27, 549 28, 549 43, 549 46, 549 48, 549354, 549356, 549386, 549459, A61K 3100
Patent
active
059901047
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The invention relates to novel polycyclic alkaloids which can bind or antagonize the NMDA (N-methyl-(D)-aspartic acid) receptor complex or otherwise protect neurons against excitatory amino acid receptor-induced degeneration. In another aspect, the invention relates to a method of inhibiting NMDA receptor activation in a mammal using the novel polycyclic alkaloids of the invention.
BACKGROUND OF THE INVENTION
Excitatory amino acids such as L-glutamate (Glu) and L-aspartate (Asp), are major neurotransmitters in the mammalian central nervous system. Multiple acidic amino acid receptor subtypes exist for these acid amino acid neurotransmitters. For example, these include ion channel-linked receptors mediating neuronal depolarization, named after the protypical agonists N-methyl-D-aspartate (NMDA), alpha-amino-5-methyl-4-isoxazolepropionic acid (AMPA), kainate and a putative presynaptic stimulator, L-2-amino-4-phosphonobutyrate (L-AP4). A fifth excitatory amino acid receptor is the metabotropic receptor, linked to phosphoinositide metabolism (Farooqui and Horrocks, Brain Res. Rev. 16, 171, 1991).
NMDA receptors play a specialized role due to the unique properties of their linked ion channels and participate in various plastic neuronal events including initiation of long-term potentiation, which is a proposed substrate of learning and memory and the establishing of synaptic contacts during neuronal development. NMDA receptors are also involved in other processes such as the transmission of sensory information (MacDermott and Dale, Trends Neurosci. 10, 280, 1987).
Apart from their important physiological roles, excitatory acidic amino acids such as NMDA are also involved in pathophysiological events in the central nervous system.
Abnormally low levels of glutamic acid (Glu) can compromise normal levels of excitation and cause, for example, learning and memory deficits. Excessive levels of Glu can produce toxic effects. The term "excitotoxicity" was coined by Olney (in Hyhan W. L. [ed]: "Heritage Disorders of Amino Acids Metabolism" New York: Macmillan pp. 501-512, 1989) to describe the process by which excitatory amino acids can cause neuronal cell death.
Evidence indicates that NMDA receptors exist in the peripheral tissues and that activation of these receptors may be involved in a mechanism of lung and other organ injury (Said, S. I. et al., Letters to Neuroscience, 65, 943-946, 1995). This cytotoxic process is mainly mediated by an over-stimulation of NMDA receptors and may occur in cases of cerebral stroke, cerebral ischaemia, epilepsy, Alzheimer's disease, AIDS-related dementias, traumatic brain injury and other neurodegenerative disorders (Olney, Ann. Rev. Pharmacol. Toxicol. 30: 47-71, 1990; Foster et al, in "Current and future Trends in Anticonvulsant, Anxiety and Stroke Therapy" Wiley-Liss, Inc. pp. 301-329, 1990; Rogawski and Porter, Pharmacol. Rev., 42: 223-286, 1990).
The NMDA receptor comprises several binding domains that interact with each other for proper functioning and modulation of nerve cell activity. It is theorized that the NMDA receptor forms a complex acting as a receptor-linked ion channel. Essentially, the function of the receptor is to bind NMDA or the natural amino acids, Glu or Asp, and open an associated ion channel that allows the entry of sodium (Na.sup.+) and calcium (Ca.sup.2+) into the stimulated neuron as well as the exit of potassium (K.sup.+).
Whereas the ion channels of other excitatory amino acid receptors (AMPA, kainate and L-AP4) are only permeable to Na.sup.+ and K.sup.+, the NMDA receptor channel is also permeable to Ca.sup.2+. This feature may be of importance for the proposed role of this receptor in both short and long-term plasticity such as learning, memory and neuropathology.
Intracellular Ca.sup.2+ is responsible for the regulation of a large variety of cellular activities (Farooqui and Horrocks, Brain Res. Rev. 16, 171; 1991). An overstimulation of brain NMDA receptors, observed in cases of anoxia, ischaemia and hypoglycemia, results
REFERENCES:
patent: 3836670 (1974-09-01), Freed et al.
patent: 4957909 (1990-09-01), Abou-Gharbia et al.
Malis et al., "Animal Pharmacology of Wy-16,225, A New Analgesic Agent", The Journal of Pharmacology and Experimental Therapeutics, vol. 194, No. 3, pp. 488-498, (1975).
A.A. Farooqui & L.A. Horrocks, "Brain Research Reviews" 16, Excitatory amino acid receptors, neural membrane phospholipid metabolism and neurological disorders, 1991, pp. 171-191.
A.B. MacDermott & N. Dale, "TINS" 10 (7), Receptors, ion channels and synaptic potentials underlying the integrative actions of excitatory amino acids, 1987, pp. 280-284.
S.I. Said, H.I. Berisha & H. Pakbaz, "Neuroscience" 65 (4), N-Methly-D-Aspartate Receptors Outside The The Central Nervous System: Activation Causes Lung Injury That is Mediated by Nitric Oxide Synthesis and Prevented by Vasoactive Intestinal Peptide, 1995, pp. 943-946.
J.W. Olney, "Annu. Rev. Pharmacol. Toxicol." 30, Excitotixic Amino Acids and Neuropsychiatric Disorders, 1990, pp. 47-71.
A.C. Foster, R. Gill, L.L. Iversen, J.A. Kemp, E.H.F. Wong & G.N. Woodruff, "Current and Future Trends in Anticonvulsant, Anxiety, and Stroke Therapy", Therapeutic Potential of NMDA Receptor Antagonists as Neuroprotective Agents, 1990, pp. 301-329.
M.A. Rogawski & R.J. Porter, "Pharmacological Reviews", 42(3), Antiepileptic Drugs: Pharmacological and Clinical Efficacy with Consideration of Promising Developmental Stage Compounds, 1990, pp. 222-286.
J.W. Downing, J.G. Brock-Utne, A. Barclay and I.L. Schwegmann, "Brit J. Anaesth", WY 16225 (Dezocine), A New Synthetic Opiate Agonist-Antagonist and Potent Analgesic: Comparison With Morphine for Relief of Pain After Lower Abdominal Surgery, 1981, pp. 59-64.
M.E. Freed, J.R. Potoski, E.H. Freed, G.L. Conklin & J.L. Malis, "Journal of Medicinal Chemistry" 16(6), Bridged Aminotetralins as Novel Potent Analgesic Substances, 1973, pp. 595-599.
W. Koek & F.C. Colpaert, "The Journal of Pharmacology and Experimental Therapeutics" 252(1), Selective Blockade of N-Methyl-D-Aspartate (NMDA)-Induced Convulsions by NMDA Antagonists and Putative Glycine Antagonists: Relationship with Phencyclidine-Like Behavioral Effects, 1990, pp. 349-357.
P.J. Fray, B.J. Sahakian, T.W. Robbins, G.F. Koob & S.D. Iversen, "Psychopharmacology" 69, An Observational Method for Quantifying the Behavioural Effects of Dopamine Agonists: Contrasting Effects of d-Amphetamine and Apomorphine, 1980, pp. 253-259.
N.W. Dunham & T.S. Miya; "Journal of the American Pharmaceutical Association" XLVI(3), A Note on a Simple Apparatus for Detecting Neurological Deficit in Rats and Mice, 1957, pp. 208-209.
J. Hughes, H.W. Kosterlitz & F.M. Leslie, "Brit J. Pharmac." 53, Effect of Morphine on Adrenergic Transmission in the Mouse Vas Deferens. Assessment of Agonist and Antagonist Potencies of Narcotic Analgesics, 1975, pp. 371-381.
J.W. Olney, Patterns Clin. Expression Genet. Var., Toxic Effects of Glutamate and Related Amino Acids on the Developing Central Nervous System, 1974, pp. 501-512.
R.L. Follenfant, G.W. Hardy, L.A. Lowe, C. Schneider & T.W. Smith, "Brit. J. Pharmacol.", 93, Antinociceptive effects of the novel opioid peptide BW443C compared with classical opiates; peripheral versus central actions, 1988, pp. 85-92.
F.M. Leslie, "Pharmacological Reviews", 39(3), Methods Used for the Study of Opioid Receptors, 1987 pp. 197-249.
C.J. Fowler & G.L. Fraser, "Neurochem. Int." 24(5), Opioid Receptors and Their Subtypes, A Critical Review with Emphasis on Radioligand Binding Experiments, 1994, pp. 401-427.
R.B. Raffa, A. Kim, K.C. Rice, B.R. De Costa, E.E. Codd & R.B. Rothman, "Peptides" 15(3), Low Affinity of FMRFamide and Four FaRPs (FMRFamide-Related Peptides), Including the Mammalian-Derived FaRPs F-8-Famide (NPFF) and A-18-Famide, for Opioid Receptors, 1994, pp. 401-404.
R.B. Rothman, V. Bykov, B.R. De Costa, A.E. Jacobson, K.C. Rice & L.S. Brady, "Peptides" 11, Interaction of Endogenous Opioid Peptides and Other Drugs With Four Kappa Opioid Binding Sites in
DiMaio John
Dixit Dilip M.
Biochem Pharma Inc.
Delacroix-Muirheid C.
Tsang Cecilia J.
LandOfFree
Polycyclic alcaloid-derivatives as NMDA-receptor antagonists does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Polycyclic alcaloid-derivatives as NMDA-receptor antagonists, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Polycyclic alcaloid-derivatives as NMDA-receptor antagonists will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1222078