Method for design of substances that enhance memory and...

Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 4 to 5 amino acid residues in defined sequence

Reexamination Certificate

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C530S317000, C530S331000, C514S002600, C514S018700, C434S278000, C434S281000, C073S866400

Reexamination Certificate

active

06320024

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to memory enhancement and to improvement in the quality of life for human individuals who for various reasons including aging, disease, or injury show impairment of memory. More specifically, the invention relates to development of a topographic model on the basis of which it is possible to design and synthesize memory-enhancing and life-quality improving substances.
DEFINITIONS AND ABBREVIATIONS
&bgr;-A4=amyloid &bgr; protein
FAAT=footshock active avoidance training
ICV=intracerebroventricular
Ala=alanine
Cys=cysteine
Asp=aspartic acid
Glu=glutamic acid
Phe=phenylalanine
Gly=glycine
His=histidine
Ile=isoleucine
Lys=lysine
Leu=leucine
Met=methionine
Asn=asparagine
Pro=proline
Gln=glutamine
Arg=arginine
Ser=serine
Thr=threonine
Val=valine
Trp=tryptophan
Tyr=tyrosine
BACKGROUND OF THE INVENTION
Immediate post-training ICV administration of a synthetic peptide homologous to &bgr;-A4, [Gln
11
]&bgr;-(1-28) Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Gln Val His Gln Lys Leu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys (SEQ ID NO: 1)] caused amnesia for FAAT in mice in dose-dependent fashion. Also amnestic were residues &bgr;-(12-28) [Val His His Gln Lys Leu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys (SEQ ID NO: 2)], &bgr;-(18-28) [Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys (SEQ ID NO: 3)], and &bgr;-(12-20) [Val His His Gln Lys Leu Val Phe Phe (SEQ ID NO: 4)](1). These amnestic peptides have in common the tripeptidic sequence Val Phe Phe (SEQ ID NO: 5). Residue &bgr;-(1-11) [Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Gln (SEQ ID NO: 6)], which does not contain Val Phe Phe, was not amnestic (this study). FAAT experiments were performed with peptides containing the Val Phe Phe sequence from which was derived a topographic model for the binding site of amnestic peptides. Since the amnestic substances are memory-enhancing at lower concentration than those at which they cause amnesia, the model can be used to deduce the structure of potential memory-enhancing peptides and non-peptidic substances.
SUMMARY OF THE INVENTION
Structure-activity study with various peptides in memory-testing paradigms in mice has made possible generation of a topographic map for a hypothetical binding surface, Z, for amnestic peptides. On the model Z binding sites are distributed in clockwise rotation the following designated loci: (1) H-bonding; (2) aromatic; (3) cationic; (4) aromatic: and (5) anionic (
FIG. 1
, No. 1-3). Effects on retention of FAAT are rationalized in terms of fit to Z, making possible design of potential memory-modulating peptidic and non-peptidic substances. The similarity in brain function in various mammals, including human beings, as well as much previous experience in the field indicates that such substances will be effective memory-enhancers in men as well as mice. In no instance known to applicant has a model such as that above been suggested, nor have any of the memory-enhancing peptides described herein been suggested for use in improving memory.
Administration of such substances and their congeners orally, subcutaneously, intravenously, transcutaneously, intrathecally, sublingually, rectally, or intracisternally leads to a restoration of the balance between excitatory and inhibitory systems in the brain, a balance which is required for optimal acquisition and retention of learning. Their administration helps correct defects in this balance that arise, for example, as a result of aging, infections, and injury. Administration of such substances exerts recyberneticizing effects on nervous system function.
Another aspect of this invention comprises substances that have been designed to mimic the actions of the active peptides but which do not have the peptide structure and would not be subject to degradation of peptide-splitting enzymes in the gut or other tissues. Such organic chemical entities would have more prolonged desired effects at lower doses than the peptidic structures.


REFERENCES:
patent: 5063206 (1991-11-01), Bridge et al.
patent: 5137873 (1992-08-01), Yankner
patent: 5652334 (1997-07-01), Roberts
Dixon, Computer-aided drug design . . . ,Tibtech, vol. 10, 357-363, 1991.*
Pabo et al., Computer-aided . . . , Biochemistry, v. 25, 5987-5991, 1987.*
Connolly, ML, “Solvent-accessible Surfaces of Proteins and Nucleic Acids”Science221(4612):709-713 (Aug. 19, 1983).
Flood, JF et al., “Topography for a Binding Site for Small Amnestic Peptides Deduced from Structure-activity Studies: Relation to Amnestic Effect of Amyloid &bgr; Protein”PNAS USA91:380-384 (Jan. 1994).
Flood, JF et al., “Amnestic Effects in Mice ofr Four Synthetic Peptides Homologous to Amyloid &bgr; Protein from Patients with Alzheimer Disease”PNAS 88(8):3363-3366 (Apr. 1991).
Pabo CO et al., “Computer-Aided-Model Building Strategies for Protein Design”Biochemistry25:5987-5991 (1986).
Dixon, JS, “Computer-Aided Drug Design: Getting the Best Results”Tibtech10:357-363 (Oct. 1992).
Mayo et al., “Dreiding: A Generic Force Field for Molecular Simulations,” J. Phys. Chem. 1990, 94, 8897-8909.
Biograf Reference Manual, Version 1.20, BioDesign, Inc., Oct. 15, 1986.
Connolly, “Analytical Molecular Surface Calculation,”J. Appl. Cryst.(1983) 16-548-558, and Figs 2 and 3.

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