DREADD actuators
Inventors
Bonaventura, Jordi • Gomez, Juan Luis • Horti, Andrew • Hu, Feng • Michaelides, Michael • Pomper, Martin • Sanchez-Soto, Marta
Assignees
Johns Hopkins University • US Department of Health and Human Services
Publication Number
US-11739063-B2
Publication Date
2023-08-29
Expiration Date
2039-02-06
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Abstract
Disclosed is a compound of formula (I) in which R1, R2, and R3 are as described herein. Also provided are pharmaceutical compositions comprising the compound of formula (I) and methods of using the compound of formula (I), including a method of treating a disease or disorder and a method for effectuating a G-protein coupled receptor (GPCR)-mediated response in a subject.
Core Innovation
The invention provides compounds of formula (I) characterized by specific substitutions of halos and alkyl groups, pharmaceutical compositions containing these compounds, and methods of using them to treat diseases or disorders by effectuating a G-protein coupled receptor (GPCR)-mediated response in a subject. The compounds of formula (I) show high affinity (binding) for the designer receptors hM3Dq and hM4Di, which are mutated human muscarinic receptors used in DREADD technology to remotely and transiently manipulate cellular activity.
The background identifies the problem that, despite advancements in DREADD technology, there is a need for improved DREADD compositions and methods. Specifically, new compounds are needed that can be administered to treat diseases or disorders in subjects, and methods for treating such subjects are also needed.
The invention addresses these needs by providing compounds with superior brain penetrance compared to previously known compounds, suitability for DREADD-assisted metabolic mapping (DREAMM), and the ability to be labeled with radioactive isotopes with sufficient half-lives for in vivo and ex vivo imaging. This capability enables theranostic methods that combine treatment and receptor expression monitoring using PET, MRI, and MRS imaging techniques, allowing adjustment of treatment for improved efficacy. Moreover, the compounds obviate the need for fluorescent reporter proteins, avoiding associated issues such as receptor internalization, toxicity, and immune response, thus improving reproducibility and allowing quantification and validation of receptor expression non-invasively.
Claims Coverage
The claims present three main inventive features focused on methods involving compounds of formula (III) and their use with DREADD-modified human muscarinic GPCRs.
Method of reducing locomotor activity using a compound of formula (III)
A method for reducing locomotor activity by administering a compound of formula (III) or a pharmaceutically acceptable salt thereof to a subject in need.
Use of a compound of formula (III) with DREADD-modified human muscarinic GPCRs
A method for effectuating a GPCR-mediated response by administering a vector encoding a DREADD-modified human muscarinic GPCR (hM3Dq or hM4Di) to express the receptor, and subsequently administering a compound of formula (III) or a pharmaceutically acceptable salt thereof to the subject.
Imaging and dose adjustment methods combined with compound administration
Methods further comprising imaging the subject by positron emission tomography (PET), magnetic resonance imaging (MRI), and optionally magnetic resonance spectroscopy (MRS), comparing the level of modified receptor expression as determined by imaging to a control, and adjusting the dose of the compound administered accordingly. This includes administering pharmaceutical compositions containing the compound and specific isotopic labeling of substituents in the compounds for imaging purposes.
The claims collectively cover methods of treating subjects by administering compounds of formula (III), particularly in combination with DREADD-modified receptors, and performing imaging-based monitoring and dose adjustment to enhance therapeutic effectiveness.
Stated Advantages
Compounds exhibit higher affinity for hM3Dq and hM4Di receptors compared to clozapine n-oxide and known analogs.
Superior brain penetrance in non-human primates relative to prior compounds.
Suitable for DREADD-assisted metabolic mapping without undesirable effects on brain metabolism observable with other compounds.
Capability to be labeled with radioactive isotopes with longer half-lives, enabling effective in vivo and ex vivo imaging and theranostic methodologies.
Eliminates the need for fluorescent reporter proteins, avoiding related toxicity, receptor internalization, and immune response, and enabling reliable quantification of receptor expression across species.
Compounds containing fluorine-19 function as contrast agents for MRI and MRS due to the absence of endogenous 19F in living organisms, providing a powerful, non-invasive imaging option.
Documented Applications
Treatment of diseases or disorders in subjects, particularly diseases or disorders of the brain such as schizophrenia, bipolar disorder, and epilepsy.
Efficient actuation of designer receptors exclusively activated by designer drugs (DREADDs) to remotely and transiently manipulate cellular activity.
Non-invasive imaging and monitoring of receptor expression and function in live subjects using PET, MRI, and MRS including theranostic applications to adjust dosing regimens.
DREADD-assisted metabolic mapping (DREAMM) to evaluate whole-brain functional circuit activity.
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