Selective D3 dopamine receptor agonists and methods of their use

Inventors

Sibley, David R. • Moritz, Amy Elizabeth • Free, R. Benjamin • Steiner, Joseph P. • Southall, Noel Terrence • Ferrer, Marc • Hu, Xin • Weiner, Warren S. • Aubé, Jeffrey • Frankowski, Kevin

Assignees

University of North Carolina at Chapel Hill • University of Kansas • US Department of Health and Human Services

Abstract

The disclosure of a compound of Formula I or a pharmaceutically acceptable salt thereofThe variables W, R1, R2, R3, and R4 are defined in the disclosure. The disclosure provides a compound or salt of Formula I together with a pharmaceutically acceptable carrier. The disclosure also provides methods of treating a patient for Parkinson's disease and related syndromes, dyskinesia, especially dyskinesias secondary to treating Parkinson's disease with L-DOPA, neurodegenerative disorders such as Alzheimer's disease and dementia, Huntington's disease, restless legs syndrome, bipolar disorder and depression, schizophrenia, cognitive dysfunction, or substance use disorders, the methods comprising administering a compound of Formula I or salt thereof to the patient. The disclosure provides combination methods of treatment in which the compound of Formula I is administered to the patient together with one or more additional active agents.

Core Innovation

The invention provides compounds of Formula I or pharmaceutically acceptable salts thereof, characterized by specified variables W, R1, R2, R3, and R4. These compounds exhibit high selectivity for functionally activating the dopamine D3 receptor (D3 DAR). Certain compounds promote β-arrestin translocation to D3 DAR with an EC50 less than 200 nM, and have efficacy comparable to dopamine, but exhibit minimal to no agonist activity at the related D2 DAR. They also show potent agonist activity in D3 DAR G protein-mediated signaling and ERK1/2 phosphorylation assays while lacking functional activity at other dopamine receptor subtypes except for minimal D2 DAR inhibition at concentrations over 10 µM.

The problem addressed is the lack of highly selective D3 DAR agonists. Dopamine receptors are GPCRs that regulate critical nervous system functions, but existing drugs that target D3 DARs lack selectivity over the closely related D2 DAR due to high homology, particularly in the orthosteric binding site. Conventional D3-preferring D2/D3 DAR agonists can induce impulse control disorders, possibly linked to D2 DAR stimulation, thus creating a need for compounds that selectively activate D3 DAR without significant D2 DAR activity.

The invention solves this by providing compounds that bind and activate D3 DAR in a unique manner distinct from dopamine and conventional agonists, offering high selectivity and efficacy. Molecular modeling and mutagenesis studies support this unique mode of interaction. Furthermore, compounds of Formula I demonstrate neuroprotective effects in cell-based assays superior to pramipexole, a less selective agonist, indicating therapeutic potential in neurodegenerative and related disorders.

Claims Coverage

The patent includes 21 claims focused on methods of treating various disorders using compounds of Formula I, with independent claims reciting therapeutic uses and chemical features of the compounds.

The inventive claims primarily cover therapeutic methods employing highly selective D3 DAR agonists of Formula I for a range of central nervous system disorders, with structural specifications ensuring selectivity and therapeutic efficacy, alone or in combination with other agents.

Stated Advantages

Documented Applications