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DB24-0175 Bonifazi_supplementary_information_v2.pdf (15.28 MB)

Development of novel tools for dissection of central versus peripheral dopamine D2-like receptor signaling in dysglycemia

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posted on 2024-06-11, 18:20 authored by Alessandro Bonifazi, Michael Ellenberger, Zachary J. Farino, Despoina Aslanoglou, Rana Rais, Sandra Pereira, José O. Mantilla-Rivas, Comfort A. Boateng, Amy J. Eshleman, Aaron Janow

Dopamine (DA) D2-like receptors in both the central nervous system (CNS) and the periphery are key modulators of metabolism. Moreover, disruption of D2-like receptor signaling is implicated in dysglycemia. Yet, the respective metabolic contributions of CNS versus peripheral D2-like receptors including D2 (D2R) and D3 (D3R) receptors remain poorly understood. To address this, we developed new pharmacological tools, D2-like receptor agonists with diminished and delayed blood-brain barrier capability, to selectively manipulate D2R/D3R signaling in the periphery. We designated bromocriptine methiodide (BrMeI), a quaternary methiodide analogue of D2R/D3R agonist and diabetes drug bromocriptine, as our lead compound based on preservation of D2R/D3R binding and functional efficacy. We then used BrMeI and unmodified bromocriptine to dissect relative contributions of CNS versus peripheral D2R/D3R signaling in treating dysglycemia. Systemic administration of bromocriptine, with unrestricted access to CNS and peripheral targets, significantly improved both insulin sensitivity and glucose tolerance in obese, dysglycemic mice in vivo. In contrast, metabolic improvements were attenuated when access to bromocriptine was restricted either to the CNS through intracerebroventricular administration or delayed access to the CNS via BrMeI. Our findings demonstrate that the coordinated actions of both CNS and peripheral D2-like receptors are required for correcting dysglycemia. Ultimately, the development of a first-generation of drugs designed to selectively target the periphery provides a blueprint for dissecting mechanisms of central versus peripheral DA signaling and paves the way for novel strategies to treat dysglycemia.


Highlights

· We developed new pharmacological tools with diminished blood-brain barrier capability to selectively manipulate peripheral dopamine D2-like receptor signaling.

· Our lead compound, bromocriptine methiodide (BrMeI), shows preserved dopamine D2-like receptor binding and functional efficacy.

· We used BrMeI and unmodified bromocriptine to dissect relative contributions of CNS versus peripheral dopamine signaling in treating dysglycemia.

· Systemic administration of dopaminergic agonist bromocriptine significantly improves dysglycemia while metabolic improvements are attenuated after restricting access to the brain or periphery via BrMeI.

· Tandem, coordinated actions of both brain and peripheral D2-like receptors are required for correcting dysglycemia.

Funding

Department of Defense x PR141292 PR210207

DOJ/DEA x D-15-OD-0002

NIDA Addiction Treatment Discovery Program (ATDP) x

NIDA Intramural Research Program x Z1ADA000424

NIDA Medications Development Program x Z1ADA000611

NIH x DP1DA058385 K08DA031241 R01DK124219

NIH/NIDA x ADA12013

The Pittsburgh Foundation

U.S. Department of Veterans Affairs 1IK6BX005754 I01BX002758

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