Modified ligand-gated ion channels and methods of use
AssigneeHoward Hughes Medical Institute
InventorsScott Sternson, Peter Lee, Christopher Magnus
Life of this patent
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Abstract
This document relates to materials and methods for modulating ligand gated ion channel (LGIC) activity. For example, modified LGICs including at least one LGIC subunit having a modified ligand binding domain (LBD) and/or a modified ion pore domain (IPD) are provided. Also provided are exogenous LGIC ligands that can bind to and activate the modified LGIC, as well as methods of modulating ion transport across the membrane of a cell of a mammal, methods of modulating the excitability of a cell in a mammal, and methods of treating a mammal having a channelopathy.
Claims37
A modified ligand gated ion channel (LGIC) comprising at least one modified LGIC subunit, said modified LGIC subunit comprising:
- a ligand binding domain (LBD) comprising an amino acid modification wherein the LBD is an alpha7 nicotinic acetylcholine receptor (α7-nAChR) LBD comprising a L131G amino acid substitution, a Q139L amino acid substitution, and a Y217F amino acid substitution, and
- an ion pore domain (IPD), wherein the IPD is an IPD from a receptor selected from the group consisting of a serotonin 3 receptor (5HT3) IPD, a glycine receptor (GlyR) IPD, a gamma-aminobutyric acid (GABA) receptor IPD, and an alpha7 nicotinic acetylcholine receptor (α7-nAChR) IPD.
2-24. (canceled)
26-55. (canceled)
A ligand having increased potency for a modified ligand gated ion channel (LGIC), wherein the ligand comprises Formula V:
- wherein R1=H, phenyl, 2-toluyl;
- 3-pyridyl;
- 4-pyridyl;
- trifluoromethyl;
- methoxy;
- ethoxy;
- propoxy, isopropoxy;
- N,N-dimethylamino;
- N,N-diethylamino;
- imidazole, pyrrole, pyrazole, triazole, or isoxazole-3-amine;
- and
- wherein R2=H, methyl, or phenyl;
- and
- wherein the compound is selected from the group consisting of compound 815, compound 816, and compound 817.
57-129. (canceled)
A synthetic nucleic acid construct comprising a nucleic acid sequence having at least 75 percent sequence identity to the sequence set forth in SEQ ID NO:27, wherein said nucleic acid sequence comprises a nucleic acid sequence encoding a ligand binding domain (LBD) comprising an amino acid modification, and wherein said nucleic acid sequence comprises a nucleic acid sequence encoding ion pore domain (IPD).
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A synthetic nucleic acid construct comprising a nucleic acid sequence having at least 75 percent sequence identity to the sequence set forth in SEQ ID NO:28, wherein said nucleic acid sequence having at least 75 percent sequence identity to the sequence set forth in SEQ ID NO:28 comprises a nucleic acid sequence encoding a ligand binding domain (LBD) comprising an amino acid modification, and wherein said nucleic acid sequence comprises a nucleic acid sequence encoding ion pore domain (IPD).
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A synthetic nucleic acid construct comprising a nucleic acid sequence having at least 75 percent sequence identity to the sequence set forth in SEQ ID NO:29, wherein said nucleic acid sequence comprises a nucleic acid sequence encoding a ligand binding domain (LBD) comprising an amino acid modification, and wherein said nucleic acid sequence comprises a nucleic acid sequence encoding ion pore domain (IPD).
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A synthetic nucleic acid construct comprising the sequence set forth in SEQ ID NO:
- 33.
A synthetic nucleic acid construct comprising the sequence set forth in SEQ ID NO:
- 34.
Dependencies are inferred from the claim text.