Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-04-05
2001-08-14
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S338000, C514S375000, C514S450000, C514S452000, C514S464000, C514S465000, C540S546000, C540S599000, C544S105000, C546S198000, C546S271700, C548S217000
Reexamination Certificate
active
06274600
ABSTRACT:
FIELD OF INVENTION
The present invention relates to novel compounds which are useful, for example, in the prevention of cerebral insufficiency, to enhance receptor functioning in synapses in those brain networks responsible for higher order behaviors, and the like. In a particular aspect, the invention relates to methods for the use of the compounds disclosed herein, and to methods for the preparation thereof.
BACKGROUND OF THE INVENTION
Excitatory synaptic currents at many (probably most) sites in telencephalon (cortex, limbic system, striatum; about 90% of human brain) and cerebellum occur when the transmitter glutamate is released by input axons onto what are usually referred to as the &agr;-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA), or AMPA/quisqualate, receptors. Drugs that enhance these receptor currents will facilitate communication in brain networks responsible for perceptual-motor integration and higher order behaviors. It is also known from the literature (see Arai and Lynch in Brain Research, in press) that such drugs will promote the formation of long-term potentiation, a physiological effect widely held to encode memory.
For example, Ito et al., J. Physiol. Vol. 424:533-543 (1990), discovered that aniracetam, N-anisoyl-2-pyrrolidinone, enhances AMPA receptor mediated currents without affecting currents generated by other classes of receptors. Unfortunately, however, the drug is effective only at high concentrations (~1.0 mM) applied directly to the brain. The low potency, limited solubility, and peripheral metabolism of aniracetam limit its utility as an experimental tool and its potential value as a therapeutic. There is a need, therefore, for the design and synthesis of new drugs that are more potent, more soluble and less readily metabolized than aniracetam. Such compounds would provide new tools for manipulating the properties of the AMPA receptor and would be a major step towards a drug that could enhance AMPA receptor function in the brain after peripheral administration.
BRIEF DESCRIPTION OF THE INVENTION
We have discovered novel compounds that are several times more potent than aniracetam in enhancing synaptic responses (i.e, they produce larger effects than aniracetam at lower concentrations). The invention compounds increase the strength of long-term potentiation and increase synaptic responses in the brain following peripheral administration. Invention compounds can be used, for example, to facilitate behaviors dependent upon AMPA receptor, as therapeutics in conditions in which receptors or synapses utilizing them are reduced in numbers, and the like.
REFERENCES:
patent: 5098464 (1992-03-01), Barton et al.
patent: 5744610 (1998-04-01), Barton et al.
patent: 5747492 (1998-05-01), Lynch et al.
patent: 5773434 (1998-06-01), Larson et al.
patent: 5852008 (1998-12-01), Lynch et al.
patent: 5891876 (1999-04-01), Lynch et al.
Lynch Gary S.
Rogers Gary A.
Rao Deepak R.
Shah Mukund J.
The Regents of the University of California
Townsend and Townsend / and Crew LLP
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