An insurmountable NPY Y5 receptor antagonist exhibits superior anti-obesity effects in high-fat diet-induced obese mice

Fukasaka, Yumiko; Nambu, Hirohide; Tanioka, Hiroaki; Obata, Atsushi; Tonomura, Misato; Okuno, Takayuki; Yukioka, Hidekazu

doi:10.1016/j.npep.2018.05.006

Cited by 19 publications

(3 citation statements)

References 31 publications

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“…It has been proposed that insurmountable antagonism may play an important role in sustained receptor occupancy and result in marked in vivo efficacy with neuropeptide Y5 receptors (Fukasaka et al, 2018), neurokinin 1 receptors (Lindström et al, 2007), and endothelin receptors (Iglarz et al, 2014). Furthermore, it has been reported that the AT 1 receptor antagonist candesartan cilexetil exhibits insurmountable antagonism and has a remarkable ability to decrease blood pressure and extend the duration of action compared to the surmountable AT 1 receptor antagonist, losartan without differences in the tolerability profiles according to clinical studies (Gradman, 2002).…”

Section: Discussionmentioning

confidence: 99%

In Vitro Pharmacological Profile of KW-6356, a Novel Adenosine A_2AReceptor Antagonist/Inverse Agonist

et al. 2023

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KW-6356 is a novel adenosine A 2A receptor (A 2A receptor) antagonist/inverse agonist, and its efficacy as monotherapy in Parkinson's disease (PD) patients has been reported. Istradefylline is a first-generation A 2A receptor antagonist approved for use as adjunct treatment to levodopa/decarboxylase inhibitor in adult PD patients experiencing OFF episodes. In this study, we investigated the in vitro pharmacological profile of KW-6356 as an A 2A receptor antagonist/inverse agonist and the mode of antagonism and compared them with istradefylline. In addition, we determined co-crystal structures of A 2A receptor in complex with KW-6356 and istradefylline to explore the structural basis of the antagonistic properties of KW-6356. Pharmacological studies have shown that KW-6356 is a potent and selective ligand for the A 2A receptor (the −log of inhibition constant = 9.93 ± 0.01 for human receptor) with a very low dissociation rate from the receptor (the dissociation kinetic rate constant = 0.016 ± 0.006 min -1 for human receptor). In particular, in vitro functional studies indicated that KW-6356 exhibits insurmountable antagonism and inverse agonism, while istradefylline exhibits surmountable antagonism. Crystallography of KW-6356-and istradefylline-bound A 2A receptor have indicated that interactions with His250 6.52 and Trp246 6.48 are essential for the inverse agonism, while the interactions at both deep inside the orthosteric pocket and the pocket lid stabilizing the extracellular loop conformation may contribute to the insurmountable antagonism of KW-6356. These profiles may reflect important difference in vivo and help predict better clinical performance.

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Section: Discussionmentioning

confidence: 99%

In Vitro Pharmacological Profile of KW-6356, a Novel Adenosine A_2AReceptor Antagonist/Inverse Agonist

et al. 2023

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“…Therefore, it plays a critical role in the regulation of energy homeostasis [ 47 ]. Recently, strategies targeting the NPY signaling pathway have been explored for obesity and diabetes interventions in animal studies, and some exciting metabolic benefits have been reported [ 48 – 52 ]. Since obesity and diabetes are key risk factors for cardiovascular disease, blocking the effects of NPY would not only have beneficial effects on local restenosis after arterial injury, but would also improve energy metabolism throughout the body, this reduced fat, a major potential cause of arteriosclerosis development and subsequent neointimal formation.…”

Section: Discussionmentioning

confidence: 99%

Deficiency of neuropeptide Y attenuates neointima formation after vascular injury in mice

Song

LinYu

et al. 2023

BMC Cardiovasc Disord

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Background Restenosis after percutaneous coronary intervention (PCI) limits therapeutic revascularization. Neuropeptide Y (NPY), co-stored and co-released with the sympathetic nervous system, is involved in this process, but its exact role and underlying mechanisms remain to be fully understood. This study aimed to investigate the role of NPY in neointima formation after vascular injury. Methods Using the left carotid arteries of wild-type (WT, NPY-intact) and NPY-deficient (NPY−/−) mice, ferric chloride-mediated carotid artery injury induced neointima formation. Three weeks after injury, the left injured carotid artery and contralateral uninjured carotid artery were collected for histological analysis and immunohistochemical staining. RT-qPCR was used to detect the mRNA expression of several key inflammatory markers and cell adhesion molecules in vascular samples. Raw264.7 cells were treated with NPY, lipopolysaccharide (LPS), and lipopolysaccharide-free, respectively, and RT-qPCR was used to detect the expression of these inflammatory mediators. Results Compared with WT mice, NPY−/− mice had significantly reduced neointimal formation three weeks after injury. Mechanistically, immunohistochemical analysis showed there were fewer macrophages and more vascular smooth muscle cells in the neointima of NPY−/− mice. Moreover, the mRNA expression of key inflammatory markers such as interleukin-6 (IL-6), transforming growth factor-β1 (TGF-β1), and intercellular adhesion molecule-1 (ICAM-1) was significantly lower in the injured carotid arteries of NPY−/− mice, compared to that in the injured carotid arteries of WT mice. In RAW264.7 macrophages, NPY significantly promoted TGF-β1 mRNA expression under unactivated but not LPS-stimulated condition. Conclusions Deletion of NPY attenuated neointima formation after artery injury, at least partly, through reducing the local inflammatory response, suggesting that NPY pathway may provide new insights into the mechanism of restenosis.

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“…Moreover, the NPY Y5 receptor is also known to mediate NPY-induced feeding [ 90 ]. Fukasaka et al demonstrated that NPY Y5 receptor antagonists significantly reduced weight gain and food intake [ 91 ]. Accumulating knowledge on the effect of NPY and its receptor on obesity may provide new insights into the treatment of obese women with PCOS.…”

Section: Npy Affects Metabolic Disordersmentioning

confidence: 99%

Potential for NPY receptor–related therapies for polycystic ovary syndrome: an updated review

et al. 2023

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Polycystic ovary syndrome (PCOS) is a complex endocrine disease that can cause female infertility and bring economic burden to families and to society. The clinical and/or biochemical manifestations include hyperandrogenism, persistent anovulation, and polycystic ovarian changes, often accompanied by insulin resistance and obesity. Although its pathogenesis is unclear, PCOS involves the abnormal regulation of the hypothalamic-pituitary-ovarian axis and the abnormal activation of GnRH neurons. Neuropeptide Y (NPY) is widely distributed in the arcuate nucleus of the hypothalamus and functions as the physiological integrator of two neuroendocrine systems, one governing feeding and the other controlling reproduction. In recent years, an increasing number of studies have focused on the improvement of the reproductive and metabolic status of PCOS through the therapeutic application of NPY and its receptors. In this review, we summarize the central and peripheral regulation of NPY and its receptors in the development of PCOS and discuss the potential for NPY receptor–related therapies for PCOS.

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An insurmountable NPY Y5 receptor antagonist exhibits superior anti-obesity effects in high-fat diet-induced obese mice

Cited by 19 publications

References 31 publications

In Vitro Pharmacological Profile of KW-6356, a Novel Adenosine A_2AReceptor Antagonist/Inverse Agonist

In Vitro Pharmacological Profile of KW-6356, a Novel Adenosine A_2AReceptor Antagonist/Inverse Agonist

Deficiency of neuropeptide Y attenuates neointima formation after vascular injury in mice

Potential for NPY receptor–related therapies for polycystic ovary syndrome: an updated review

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An insurmountable NPY Y5 receptor antagonist exhibits superior anti-obesity effects in high-fat diet-induced obese mice

Cited by 19 publications

References 31 publications

In Vitro Pharmacological Profile of KW-6356, a Novel Adenosine A2AReceptor Antagonist/Inverse Agonist

In Vitro Pharmacological Profile of KW-6356, a Novel Adenosine A2AReceptor Antagonist/Inverse Agonist

Deficiency of neuropeptide Y attenuates neointima formation after vascular injury in mice

Potential for NPY receptor–related therapies for polycystic ovary syndrome: an updated review

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In Vitro Pharmacological Profile of KW-6356, a Novel Adenosine A_2AReceptor Antagonist/Inverse Agonist

In Vitro Pharmacological Profile of KW-6356, a Novel Adenosine A_2AReceptor Antagonist/Inverse Agonist