Enantiomers of A2-73, analogues, and sigma agonist activity
Inventors
Assignees
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Publication Number
US-12208079-B2
Publication Date
2025-01-28
Expiration Date
Abstract
A pharmaceutical preparation comprising ⊖A2-73 substantially free of A2-73. This invention further includes a method treating Alzeheimer's disease in a subject in need of such treatment by the method of administering a therapeutically effective amount of ⊖A2-73 substantially free of A2-73.This invention yet further includes a method of classifying cells as to sigma receptor type by the method of exposing said cells to a detectable amount of ⊖A2-73 substantially free of A2-73 and determining the level of sigma receptor binding.
Core Innovation
The disclosure relates to a pharmaceutical use of enantiomer ()A2-73 substantially free of (+)A2-73, including a therapeutic indication for treating Alzheimers disease via sigma-1 receptor stimulation. A composition comprising enantiomer ()A2-73 is described, and enantiomer purity and dosing ranges are defined in the context of a therapeutically effective amount for the stated indication.
The disclosure also provides a method of determining a therapeutic effect of a sigma 1 therapy in a subject by measuring specific binding of ()A2-73 to cells. The method includes collecting a first cell population, exposing the cells to ()A2-73, determining a first level of cell binding using a competitive binding assay with a competing constitutively binding ligand, repeating exposure after a fixed cadent period to obtain a post-treated cell population, and determining post-treated cell binding using the same competitive binding assay and competing constitutively binding ligand.
The compared cell binding results are used to categorize the therapeutic effect. A positive therapeutic effect is determined when the post-treated cell binding is higher than the first level of cell binding, and a negative therapeutic effect is determined when the post-treated cell binding is lower than the first level of cell binding. The disclosure further describes cell classification by sigma receptor type using exposure to detectable ()A2-73 and measuring sigma receptor binding.
Background material addresses sigma receptor biology by describing sigma-1 and sigma-2 receptors and an extensive in vitro pharmacology framework for assessing receptor binding and activity, including binding and isolated organ bioassays. The disclosed framework includes principles for competitive binding assays and isolated organ bioassays and includes reported neuroprotective treatment outcomes in vitro using sigma receptor-focused binding/activity assessment.
Claims Coverage
The partial content provides one independent claim describing a method to determine a therapeutic effect of a sigma 1 therapy based on comparative cell binding of ()A2-73 measured by a competitive binding assay with a competing constitutively binding ligand. Dependent refinements further specify neurological-disorder subject context, enantiomer purity, and a quantitative ()A2-73 amount range.
Comparative cell binding to determine sigma 1 therapeutic effect
A method of determining a therapeutic effect of a sigma 1 therapy in a subject by collecting a first cell population, exposing it to enantiomer ()A2-73, determining a first level of cell binding using a competitive binding assay and a competing constitutively binding ligand, repeating the exposure in a fixed cadent for a period of time to obtain a post-treated cell population, determining post-treated cell binding by measuring specific binding of ()A2-73 using the same competitive binding assay and competing constitutively binding ligand, and comparing post-treated cell binding with the first level of cell binding to determine positive versus negative therapeutic effect.
Competitive binding assay with constitutively binding ligand
Measuring specific binding of ()A2-73 to the first cell population and to the post-treated cell population using a competitive binding assay and a competing constitutively binding ligand, for the purpose of comparing binding levels before and after exposure.
Positive and negative therapeutic effect classification by binding level change
Determining there is a positive therapeutic effect if the post-treated cell binding is higher than the first level of cell binding, and determining there is a negative therapeutic effect if the post-treated cell binding is lower than the first level of cell binding.
Neurological-disorder subject context
Applying the method to a subject that has, or is suspected of having, a neurological disorder.
Enantiomer purity substantially free of (+)A2-73
Using a composition of enantiomer ()A2-73 that is substantially free of (+)A2-73.
Quantified ()A2-73 amount range in the composition
Specifying that the enantiomer composition of ()A2-73 contains from about 0.5 mg to about 100 mg of ()A2-73.
Across the independent claim and its refinements, the core claim coverage centers on determining a sigma 1 therapys therapeutic effect by comparing cell binding levels of ()A2-73 measured via a competitive binding assay with a competing constitutively binding ligand, with explicit positive/negative classification. Refinements specify neurological-disorder context, substantially free enantiomer purity, and a quantified ()A2-73 amount range.
Stated Advantages
Provides a determination of whether a sigma 1 therapy has a positive or negative therapeutic effect based on comparing post-treated cell binding with a first level of cell binding.
Documented Applications
Treating Alzheimers disease via sigma-1 receptor stimulation using pharmaceutical use of enantiomer ()A2-73 substantially free of (+)A2-73.
Cell classification by sigma receptor type using exposure to detectable ()A2-73 and measuring sigma receptor binding.
In vitro receptor binding/activity assessment frameworks including binding assays and isolated organ bioassays, with reported neuroprotective treatment outcomes.
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