Method of reducing neuronal damage using omega conotoxin peptides

• US 5,189,020 A
• Filed: 08/02/1990
• Issued: 02/23/1993
• Est. Priority Date: 11/22/1989
• Status: Expired due to Term

• Current Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Original Assignee: Neurex Corp. (Perrigo Company PLC)
• Inventors: Tsubokawa, Makoto, Miljanich, George P., Fox, James A., Bowersox, Stephen S., Valentino, Karen L., Bitner, Robert S., Yamashiro, Donald H.
• Primary Examiner(s): Cashion, Jr., Merrell C.
• Assistant Examiner(s): ROZYCKI, ANDREW
• Application Number:
  US07/561,766
• Time in Patent Office: 936 Days
• Field of Search: 514/12, 514/21, 514/13, 514/14, 514/15, 530/324, 530/325, 530/326, 530/327
• US Class Current: 514/8.3
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07K 14/435 from animals; from humans

Abstract

A partially purified omega conotoxin binding protein is disclosed. The protein, either in partially purified form or in a synaptosomal preparation, is useful in identifying compounds for use in reducing neuronal damage related to an ischemic condition, such as stroke, in a human patient.

Claims

1. A method of reducing neuronal damage related to an ischemic condition affecting the central nervous system in a mammalian subject, comprising:

administering to the subject in a pharmaceutically effective amount, an omega conotoxin (OCT) peptide, including a fragment thereof, effective (i) to bind to an omega conotoxin binding protein, with a binding constant which is within the range of binding affinities of MVIIA, MVIIB, GVIA, GVIIA and RVIA omega conotoxins, (ii) to inhibit voltage-gated calcium currents selectively in neuronal tissue with an ED₅₀ value which is within the range of ED₅₀ values of MVIIA, MVIIB, GVIA, GVIIA and RVIA omega conotoxins, and (iii) to inhibit neurotransmitter release selectively in neuronal tissue, with an IC₅₀ which is within the range of MVIIA, MVIIB, GVIA, GVIIA and RVIA omega conotoxins.

2. The method of claim 1, wherein the peptide has such binding affinity, and ED₅₀, and IC₅₀ values in producing such inhibition as an omega conotoxin selected from the group consisting of MVIIA and GVIA omega-conotoxins.

3. The method of claim 1, wherein the peptide is a fragment of an omega conotoxin having (i) at least 11 contiguous amino acid residues from an omega conotoxin peptide, and (ii) at least one internal disulfide linkage.

4. The method of claim 3, wherein the peptide is a fragment of an omega conotoxin having (i) at least 16 contiguous amino acid residues from an omega conotoxin, and (ii) at least two internal disulfide linkages.