Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-12-06
2001-06-26
Davenport, Avis M. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S017400, C514S018700, C514S212010, C514S238500, C514S634000
Reexamination Certificate
active
06251854
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to compounds which inhibit excessive activation of glutamate receptors, particularly those in the brain. More specifically, the invention relates to compounds which block activity at N-methyl-D-aspartate receptor channels in cerebral neuronal cells.
BACKGROUND OF THE INVENTION
Excitotoxic neuronal death is a phenomenon which is associated with several chronic neurodegenerative conditions (e.g., AIDS-associated dementia, Alzheimer's disease, epilepsy, Parkinson's disease, Huntington's disease, neuropathic pain syndrome, encephalopathy, and other dementias) as well as acute cerebral dysfunctions (e.g., stroke, cerebral ischemia, hypoxia, anoxia, carbon monoxide poisoning and hypoglycemia). Excitotoxic neuronal death is triggered primarily by massive Ca
2+
influx arising from overactivation of glutamate receptor channels of the N-methyl-D-aspartate (“NMDA”) subtype (see e.g., “The NMDA Receptor”, Collingridge, G. L., ed. (Oxford Univ. Press, 1996); and Lipton and Rosenberg,
New Engl. J. Med.
(1994) 330:613-22).
Clinical use of existing non-peptidic NMDA specific channel blockers (e.g., phenyclipine (PCP) and dizolcipine (MK-801)) is limited by the frequent occurrence of adverse side effects which impair cognitive functions in treated patients. Clinical use of less specific channel blockers (e.g., dextrorphan and dextromethorphan) is limited by side effects stemming from their interactions with receptors other than NMDA receptors. At present, NMDA-specific peptidic channel blockers are not available.
SUMMARY OF THE INVENTION
A realistic strategy for neuroprotection (i.e., protection of neuronal cells from injury or death resulting from pathologic events such as excessive Ca
2+
influx) requires intervention at specific targets in neuronal cells. The NMDA receptor channel is of particular interest in this regard due to its role as a primary effector in mediating the influx of calcium that activates intracellular signaling cascades which lead to cell death.
Open channel blockers of the NMDA receptor, which act preferentially on overactivated receptors, have proved to be valuable in preventing neuronal cell death after excitotoxic insults (for example, memantine is prescribed for the treatment of Parkinson's disease). This neuroprotectant effect has been documented in vitro for hippocampal, cortical and retinal ganglion cell neurons, in animal stroke models and in humans (Miller et al.,
Pharmacopsychiatry
, (1995) 28:113-24).
The compounds of the invention act as open channel blockers and as neuroprotectants at concentrations that compare favorably with those used clinically for memantine therapy. Advantageously, the compounds of the invention are relatively small, simple molecules which are simple to manufacture and are less immunogenic than known neuroprotectant drugs.
Structurally, the compounds of the invention consist of arginine-rich oligopeptides or compounds of formula 1
where R
1
is alkyl, alkenyl, or hydroxyalkyl, aminoalkyl, or alkoxy-alkyl; and R
2
and R
3
are each natural or artificial amino acid side chains; and pharmaceutically acceptable salts thereof. Preferred compounds of the invention block the NMDA receptor channel with a K
i
of about 10-100 nM or less and are selective for NMDA receptors, having little or no effect on other receptors. Channel blockade by the compounds of the invention is voltage-dependent indicating that the compounds act as open channel blockers.
REFERENCES:
patent: 5011834 (1991-04-01), Weber et al.
patent: 5093525 (1992-03-01), Weber et al.
patent: 5190976 (1993-03-01), Weber et al.
Blondelle Sylvie
Ferrer-Montiel Antonio
Houghten Richard
Merino Jaime
Montal Mauricio
Davenport Avis M.
Foley & Lardner
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