更新于：2024-11-01

NPFFR2 x NPFFR1

更新于：2024-11-01

基本信息

关联

项与 NPFFR2 x NPFFR1 相关的药物

RF9

靶点

NPFFR1 x NPFFR2

作用机制

NPFFR1抑制剂 [+1]

在研机构-

原研机构

Centre National de la Recherche Scientifique

在研适应症-

非在研适应症

慢性疼痛

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 NPFFR2 x NPFFR1 相关的临床结果

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100 项与 NPFFR2 x NPFFR1 相关的转化医学

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0 项与 NPFFR2 x NPFFR1 相关的专利（医药）

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项与 NPFFR2 x NPFFR1 相关的文献（医药）

2024-08-08·The World Journal of Biological Psychiatry

Late maternal separation provides resilience to chronic variable stress-induced anxiety- and depressive-like behaviours in male but not female mice

Article

作者: Dongre, Shweta ; Srivastava, Raj Kamal ; Singh, Padmasana ; Ojha, Rajesh Kumar

Maternal separation can have long-lasting effects on an individual's susceptibility to stress later in life. Maternal separation during the postnatal period is a commonly used paradigm in rodents to investigate the effects of early life stress on neurobehavioural changes and stress responsiveness. However, maternal separation during stress hyporesponsive and responsive periods of postnatal development may differ in its effects on stress resilience. Therefore, we hypothesised that late maternal separation (LMS) from postnatal day 10 to 21 in mice may have different effect on resilience than early maternal separation during the first week of postnatal life. Our results suggested that male LMS mice are more resilient to chronic variable stress (CVS)-induced anxiety and depressive-like behaviour as confirmed by the open field, light-dark field, elevated plus maze, sucrose preference and tail suspension tests. In contrast, female LMS mice were equally resilient as non-LMS female mice. We found increased expression of NPY, NPY1R, NPY2R, NPFFR1, and NPFFR2 in the hypothalamus of male LMS mice whereas the opposite effect was observed in the hippocampus. LMS in male and female mice did not affect circulating corticosterone levels in response to psychological or physiological stressors. Thus, LMS renders male mice resilient to CVS-induced neurobehavioural disorders in adulthood.

2024-05-09·Journal of Medicinal Chemistry

Multitarget μ-Opioid Receptor Agonists─Neuropeptide FF Receptor Antagonists Induce Potent Antinociception with Reduced Adverse Side Effects

Article

作者: Schneider, Séverine ; Ces, Aurelia ; Ballet, Steven ; Gonzalez, Simon ; Lecat, Sandra ; Daubeuf, François ; Kremer, Mélanie ; Elhabazi, Khadija ; Herby, Claire ; De Neve, Jolien ; Bihel, Frédéric ; Fellmann-Clauss, Rosine ; Petit-Demouliere, Nathalie ; Simonin, Frédéric ; Utard, Valérie ; Martin, Charlotte

The design of bifunctional compounds is a promising approach toward the development of strong analgesics with reduced side effects. We here report the optimization of the previously published lead peptide KGFF09, which contains opioid receptor agonist and neuropeptide FF receptor antagonist pharmacophores and is shown to induce potent antinociception and reduced side effects. We evaluated the novel hybrid peptides for their in vitro activity at MOP, NPFFR1, and NPFFR2 and selected four of them (DP08/14/32/50) for assessment of their acute antinociceptive activity in mice. We further selected DP32 and DP50 and observed that their antinociceptive activity is mostly peripherally mediated; they produced no respiratory depression, no hyperalgesia, significantly less tolerance, and strongly attenuated withdrawal syndrome, as compared to morphine and the recently FDA-approved TRV130. Overall, these data suggest that MOP agonist/NPFF receptor antagonist hybrids might represent an interesting strategy to develop novel analgesics with reduced side effects.

2024-04-01·European Journal of Medicinal Chemistry

Guanidine-to-piperidine switch affords high affinity small molecule NPFF ligands with preference for NPFF1-R and NPFF2-R subtypes

Article

作者: McCurdy, Christopher R ; Awad, Ahmed ; Pallares, Victoria L C ; Seabra, Maria A B L ; Senetra, Alexandria ; Galal, Kareem A ; Obeng, Samuel

The Neuropeptide FF (NPFF) receptor system is known to modulate opioid actions and has been shown to mediate opioid-induced hyperalgesia and tolerance. The lack of subtype selective small molecule compounds has hampered further exploration of the pharmacology of this receptor system. The vast majority of available NPFF ligands possess a highly basic guanidine group, including our lead small molecule, MES304. Despite providing strong receptor binding, the guanidine group presents a potential pharmacokinetic liability for in vivo pharmacological tool development. Through structure-activity relationship exploration, we were able to modify our lead molecule MES304 to arrive at guanidine-free NPFF ligands. The novel piperidine analogues 8b and 16a are among the few non-guanidine based NPFF ligands known in literature. Both compounds displayed nanomolar NPFF-R binding affinity approaching that of the parent molecule. Moreover, while MES304 was non-subtype selective, these two analogues presented new starting points for subtype selective scaffolds, whereby 8b displayed a 15-fold preference for NPFF1-R, and 16a demonstrated an 8-fold preference for NPFF2-R. Both analogues showed no agonist activity on either receptor subtype in the in vitro functional activity assay, while 8b displayed antagonistic properties at NPFF1-R. The calculated physicochemical properties of 8b and 16a were also shown to be more favorable for in vivo tool design. These results indicate the possibility of developing potent, subtype selective NPFF ligands devoid of a guanidine functionality.