Metabolism Supports Macrophage Activation

Macrophages are found in most tissues of the body, where they have tissue- and context-dependent roles in maintaining homeostasis as well as coordinating adaptive responses to various stresses. Their capacity for specialized functions is controlled by polarizing signals, which activate macrophages by upregulating transcriptional programs that encode distinct effector functions. An important conceptual advance in the field of macrophage biology, emerging from recent studies, is that macrophage activation is critically supported by metabolic shifts. Metabolic shifts fuel multiple aspects of macrophage activation, and preventing these shifts impairs appropriate activation. These findings raise the exciting possibility that macrophage functions in various contexts could be regulated by manipulating their metabolism. Here, we review the rapidly evolving field of macrophage metabolism, discussing how polarizing signals trigger metabolic shifts and how these shifts enable appropriate activation and sustain effector activities. We also discuss recent studies indicating that the mitochondria are central hubs in inflammatory macrophage activation

Design, Synthesis, and Structure–Activity Relationship Studies of (4-Alkoxyphenyl)glycinamides and Bioisosteric 1,3,4-Oxadiazoles as GPR88 Agonists

International audienc

Additional file 1: of Development and validation of a high-throughput calcium mobilization assay for the orphan receptor GPR88

Development and validation of a high-throughput calcium mobilization assay for the orphan receptor GPR88. (DOC 316 kb

Discovery of Novel Proline-Based Neuropeptide FF Receptor Antagonists

The neuropeptide FF (NPFF) system has been implicated in a number of physiological processes including modulating the pharmacological activity of opioid analgesics and several other classes of drugs of abuse. In this study, we report the discovery of a novel proline scaffold with antagonistic activity at the NPFF receptors through a high throughput screening campaign using a functional calcium mobilization assay. Focused structure–activity relationship studies on the initial hit <b>1</b> have resulted in several analogs with calcium mobilization potencies in the submicromolar range and modest selectivity for the NPFF1 receptor. Affinities and potencies of these compounds were confirmed in radioligand binding and functional cAMP assays. Two compounds, <b>16</b> and <b>33</b>, had good solubility and blood–brain barrier permeability that fall within the range of CNS permeant candidates without the liability of being a P-glycoprotein substrate. Finally, both compounds reversed fentanyl-induced hyperalgesia in rats when administered intraperitoneally. Together, these results point to the potential of these proline analogs as promising NPFF receptor antagonists

Novel Diarylurea Based Allosteric Modulators of the Cannabinoid CB1 Receptor: Evaluation of Importance of 6‑Pyrrolidinylpyridinyl Substitution

Allosteric modulators of the cannabinoid CB1 receptor have recently been reported as an alternative approach to modulate the CB1 receptor for therapeutic benefits. In this study, we report the design and synthesis of a series of diarylureas derived from PSNCBAM-1 (<b>2</b>). Similar to <b>2</b>, these diarylureas dose-dependently inhibited CP55,940-induced intracellular calcium mobilization and [³⁵S]­GTP-γ-S binding while enhancing [³H]­CP55,940 binding to the CB1 receptor. Structure–activity relationship studies revealed that the pyridinyl ring of <b>2</b> could be replaced by other aromatic rings and the pyrrolidinyl ring is not required for CB1 allosteric modulation. <b>34</b> (RTICBM-74) had similar potencies as <b>2</b> in all in vitro assays but showed significantly improved metabolic stability to rat liver microsomes. More importantly, <b>34</b> was more effective than <b>2</b> in attenuating the reinstatement of extinguished cocaine-seeking behavior in rats, demonstrating the potential of this diarylurea series as promising candidates for the development of relapse treatment of cocaine addiction