Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-04-30
1999-09-21
Lambkin, Deborah C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
549 24, 549 25, A61K 3138, C07D33504
Patent
active
059554932
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to polycyclic alkaloids, and more particularly, to S-morphinan derivatives and their use in therapy as neuroprotective and anti-convulsant agents.
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 prototypical agonists N-methyl-D-aspartate (NMDA), alpha-amino-5-methyl-4-isoxazoleproprionic 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. "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 in a build-up of the concentration of Ca.sup.+2 in stimulated neurons and a cascade of lipases, proteases and endonucleases) that lead to neuronal cell death (Farooqui and Horrocks, Brain Res. Rev. 16, 171; 1991).
There is therefore a need for compounds which can bind or
REFERENCES:
patent: 4806543 (1989-02-01), Choi et al.
patent: 5177218 (1993-01-01), Fischer et al.
patent: 5219861 (1993-06-01), Kanematsu et al.
Sauter et al., "Thiamorphinans I" XP 000644576 pp. 1477-1480 (1983).
Lemaire et al., "Agonist and antogonist opioid activity of axial and equatorial conformations of S-methyl-and S-allyl-morphinans" XP 000645102 European Journal Pharmacology 258:111-118 (1994).
Farooqui et al., "Excitatory amino acid receptors, neural membrane phospholipid metabolism and neurological disorders" Brain Research Reviews 16:171-191 (1991).
MacDermott et al., "Receptors, ion channels and synaptic potentials underlying the integrative actions of excitatory amino acids" TINS 10:280-284 (1987).
Olney, "Toxic Effects of Glutamate and Related Amino Acids on the Developing Central Nervous System" pp. 501-512 (1989).
Said et al., "N-Methl-D-Aspartate Receptors Outside the Central Nervous System: Activation Causes Acute Lung Injury that is Mediated by Nitric Oxide Synthesis and Prevented by Vasoactive Intestinal Peptide" Neuroscience 65:943-946 (1995).
Olney, "Excitotoxic Amino Acids and Neuropsychiatric Disorders" Ann. Rev. Pharmacol. Toxicol 30:47-71 (1990).
Foster et al., "Therapeutic Potential of NMDA Receptor Antagonists as Neuroprotective Agents" Current and Future Trends in Anticovulsant, Anxiety, and Stroke Therapy pp. 301-329 (1990).
Rogawski et al., "Antiepileptic Drugs: Pharmacological Mechanisms and Clinical Efficacy with Consideration of Promising Developmental Stage Compounds" Pharmacol. Rev. 42:233-286 (1990).
Koek et al., "Selective Blockade of N-Methyl-D-Aspartate (NMDA)- Induced Convulsions by NMDA Antagonists and Putative Glycine Antagonists: Relationship with Phencyclidine-Like Behavioral Effects.sup.1 " The Journal of Pharmacology and Experimental Therapeutics 252:349-357 (1990).
Fray et al., "An observational Method for Quantifying the Behavioural Effects of Dopamine Agonists: Contrasting Effects of d-Amphetamine and Apomorphine" Psycopharmacology 69:253-259 (1980).
Biochem Pharma Inc.
Lambkin Deborah C.
LandOfFree
Thiamorphinans with neuroprotective activity does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Thiamorphinans with neuroprotective activity, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Thiamorphinans with neuroprotective activity will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-80717