Dopamine (DA) D2-like receptors are key physiological modulators of metabolism under healthy and disease states. While D2-like receptors are expressed both in the central nervous system (CNS) and within the periphery, the respective metabolic roles of CNS and peripheral D2-like receptors remain poorly understood. Therefore, to disentangle these CNS versus peripheral contributions, we synthesized a series of new peripherally-limited D2-like receptor agonists. We selected bromocriptine methiodide, a quaternary methiodide (MeI) analog of bromocriptine as our lead compound based on preservation of its binding and functional efficacy at D2-like receptors and its diminished blood brain barrier permeability. Systemic administration of bromocriptine, with unrestricted access to both CNS and peripheral targets, significantly improved both insulin sensitivity and glucose tolerance in obese, insulin-resistant mice in vivo. In contrast, metabolic improvements were abolished when bromocriptine’s access was restricted either to the CNS through intracerebroventricular administration or to the periphery via the peripherally-limited bromocriptine MeI. Our findings therefore suggest that the coordinated actions of both CNS and peripheral D2-like receptors are required for bromocriptine’s therapeutic efficacy in correcting dysglycemia. Overall, bromocriptine MeI may serve as a useful new tool to further dissect these mechanisms of peripheral DA signaling.
M.P. Ellenberger: None. Z. Farino: None. J. Mantilla-Rivas: None. B. Slusher: None.
Department of Defense (PR141292) , National Institutes of Health (R01DK124219)