Neuropeptide Y (NPY) is abundantly distributed in the peripheral and central nervous system (CNS) and is involved in the control of sympathetic nervous system activity, immune function, central regulation of energy balance and food intake,stress, anxiety, mood, and cognition[3]. JNJ-31020028 is a novel high affinity and low molecular weight Y2 receptor antagonist. NPY inhibits hypothalamic NE release through the Y2 receptor, acting at both the NE terminal and cell body region ,and Y2 antagonists increase NE release from hypothalamic synaptosomes[4]. JNJ-31020028 (15 mg/kg, s.c.) did reverse the anxiogenic effects of withdrawal from a single bolus dose of alcohol on the elevated plus-maze, confirming the anxiolytic-like properties of NPY Y2 antagonism[5]. The compound had poor oral bioavailability (6%) but high subcutaneous bioavailability (100%).Subcutaneous dosing was the preferred route for several of the models described in this paper and yielded good plasma levels (Cmax 4.35μmol/l) and fast absorption with a 0.83-h half-life[6].In autoradiography studies, N-(11)C-methyl-JNJ-31020028 receptor binding sites were observed primarily in the hippocampus and were inhibited by unlabeled JNJ-31020028. In PET studies, N-(11)C-methyl-JNJ-31020028 was metabolized slowly in the bloodstream, with 25% of the (11)C-labeled parent compound remaining 30 min after injection. PET imaging showed baseline binding potentials of 0.64 ± 0.07 in the thalamus, 0.55 ± 0.02 in the caudate, and 0.49 ± 0.03 in the hippocampus. Graphical reference region analyses demonstrated that N-(11)C-methyl-JNJ-31020028 binding was reversible; infusion of unlabeled JNJ-31020028 markedly displaced the PET radioligand from binding sites in the hippocampus, thalamus, caudate nucleus, and cerebellum but not in the corpus callosum, which served as reference region for nonspecific binding[7].
JNJ-31020028 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HEK293 cells
1 μM
10 minutes
To investigate the inhibitory effect of JNJ-31020028 on NPY-induced IP accumulation
Nat Commun. 2021 Feb 2;12(1):737
JNJ-31020028 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Insl5-rtTA×Tet-Cre×Dq mouse model
Intraperitoneal injection
20 mg/kg
Single dose
Blockade of Y2R receptor, abolishing the CNO-dependent reduction in food intake
Diabetologia. 2020 Jul;63(7):1396-1407
Male Wistar rats
Diet-induced obese (DIO) model
Osmotic minipump
2.5 mg/kg/day
Daily for 8 weeks
JNJ-31020028 prevented liver steatosis (p=0.03) without significant weight loss. Downregulation of hepatic de novo lipogenesis-regulating genes (SREBP1 and MLXIPL) was observed (p≤0.0001).
Nutrients. 2024 Mar 21;16(6):904
Mice
Acute anorexia model
Intraperitoneal injection
10 mg/kg·bw
Single administration, observed at 0.5, 1, and 2 hours
JNJ-31020028, as an NPY2 receptor antagonist, can attenuate the anorexic response induced by PYY or DON
Toxins (Basel). 2021 Jul 22;13(8):512
Mice
Ovariectomized mouse model
Intraperitoneal injection
10 mg/kg
Once daily for eight weeks
To evaluate the effect of Y2 receptor antagonism on bone formation, results showed antagonist-treated mice had reduced weight, increased whole-body bone mineral density, increased vertebral trabecular bone volume, connectivity density and trabecular thickness, increased bone volume within femoral trabecular regions, and decreased serum P1NP and CTX-1 levels
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