A novel approach to treating opioid use disorders: Dual agonists of glucagon-like peptide-1 receptors and neuropeptide Y2 receptors

Merkel, Riley; Moreno, Amanda; Zhang, Yafang; Herman, Rae J.; Nathan, Jennifer Ben; Zeb, Sana; Rahematpura, Suditi; Stecyk, Kamryn; Milliken, Brandon T.; Hayes, Matthew R.; Doyle, Robert P.; Schmidt, Heath D.

doi:10.1016/j.neubiorev.2021.10.026

Cited by 13 publications

(9 citation statements)

References 150 publications

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“…PYY 3–36 , a truncated peptide agonist derived from dipeptidyl peptidase IV (DPPIV)-mediated proteolysis of full-length PYY 1–36 , is of particular interest as it binds preferentially to the anorectic neuropeptide Y2-R (Talsania, Anini et al 2005, Kjaergaard, Salinas et al 2019, Merkel, Moreno et al 2021, Ostergaard, Paulsson et al 2021, Metzner, Herzog et al 2022). PYY 3-36 crosses the blood-brain-barrier (Nonaka, Shioda et al 2003) and inhibits food intake via its interactions with Y2-R in brain areas that regulate energy homeostasis, including the ARC of the hypothalamus and the AP and NTS of the hindbrain (Shaw, Gackenheimer et al 2003, Fetissov, Byrne et al 2004, Neary, Small et al 2005, Blevins, Chelikani et al 2008).…”

Section: Introductionmentioning

confidence: 99%

A Peptide Triple Agonist of GLP-1, Neuropeptide Y1, and Neuropeptide Y2 Receptors Promotes Glycemic Control and Weight Loss

Chichura

Elfers²,

Salameh³

et al. 2022

Preprint

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Mechanisms underlying long-term sustained weight loss and glycemic normalization after obesity surgery include changes in gut hormone levels, including glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). We demonstrate that two peptide biased agonists (GEP44 and GEP12) of the GLP-1, neuropeptide Y1, and neuropeptide Y2 receptors (GLP-1R, Y1-R, and Y2-R, respectively) elicit Y1-R antagonist-controlled, GLP-1R-dependent stimulation of insulin secretion in both rat and human pancreatic islets, thus revealing the counteracting effects of Y1-R and GLP-1R agonism. These agonists also promote insulin-independent Y1-R-mediated glucose uptake in muscle tissue ex vivo and more profound reductions in food intake and body weight than liraglutide when administered to diet-induced obese rats. Our findings support a role for Y1-R signaling in glucoregulation and highlight the therapeutic potential of simultaneous receptor targeting to achieve long-term benefits for millions of patients.

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Section: Introductionmentioning

confidence: 99%

A Peptide Triple Agonist of GLP-1, Neuropeptide Y1, and Neuropeptide Y2 Receptors Promotes Glycemic Control and Weight Loss

Chichura

Elfers²,

Salameh³

et al. 2022

Preprint

Self Cite

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“…Experimental agonists of the Y2 receptor exist for use in research, and have been considered for use as novel antidepressants, but none have been developed for use in humans [86]. It has recently been suggested that combined agonism of the Y2 receptor and the glucagon-like peptide-1 (GLP-1) receptor may be a useful approach to treating addictive behaviours in humans [87]. GLP-1 agonists have shown independent evidence of efficacy in treating obesity in randomized controlled trials [88].…”

Section: Synthetic Pharmacological Therapiesmentioning

confidence: 99%

The Genetic Basis of Future Pharmacological Strategies for the Management of Comorbid Obesity and Depression: A Scoping Review

Rajkumar¹

2023

Preprint

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Depression and obesity are highly comorbid with one another, with evidence for bidirectional causal links between each disorder and a shared biological basis. The available evidence suggests that genetic factors play a major role in influencing both the occurrence of comorbid depression and obesity, their courses, and their response to existing treatments. The current paper is a scoping review of studies that have evaluated the contribution of specific genetic variants to the comorbidity between obesity and depression. Based on a search of the PubMed and EMBASE databases, 28 studies were included in this review, covering 54 candidate genes. Positive associations were identified for fourteen genetic loci (AKR1C2, APOA5, COMT, DAT1, FTO, KCNE1, MAOA, MC4R, MCHR2, NPY2R, NR3C1, Ob, PCSK9 and TAL1). Replicated findings across two or more independent samples were observed for the FTO and MC4R genes. Many of these gene products represent novel molecular targets for the pharmacological management of obesity which are not pharmacologically influenced by existing anti-obesity or antidepressant medications. The implications of these associations for future drug development are discussed, with an emphasis on recent evidence on the polygenic architecture of comorbid depression and obesity, and on a precision medicine approach to these conditions.

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“…GLP-1 agonists are also used to treat opioid-use disorder (OUD), although their clinical effectiveness is limited by such side effects. A recent study in rats suggested that the co-targeting of GLP-1 receptors and neuropeptide Y2 receptors using a dual agonist peptide reduced opioid seeking and attenuated adverse effects and may be a more suitable way of treating OUD in human patients [ 276 ].…”

Section: Synthetic Approach Strategies and Prospects For The Developm...mentioning

confidence: 99%

Potentials of Neuropeptides as Therapeutic Agents for Neurological Diseases

Yeo

Cunliffe

et al. 2022

Biomedicines

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Despite recent leaps in modern medicine, progress in the treatment of neurological diseases remains slow. The near impermeable blood-brain barrier (BBB) that prevents the entry of therapeutics into the brain, and the complexity of neurological processes, limits the specificity of potential therapeutics. Moreover, a lack of etiological understanding and the irreversible nature of neurological conditions have resulted in low tolerability and high failure rates towards existing small molecule-based treatments. Neuropeptides, which are small proteinaceous molecules produced by the body, either in the nervous system or the peripheral organs, modulate neurological function. Although peptide-based therapeutics originated from the treatment of metabolic diseases in the 1920s, the adoption and development of peptide drugs for neurological conditions are relatively recent. In this review, we examine the natural roles of neuropeptides in the modulation of neurological function and the development of neurological disorders. Furthermore, we highlight the potential of these proteinaceous molecules in filling gaps in current therapeutics.

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A novel approach to treating opioid use disorders: Dual agonists of glucagon-like peptide-1 receptors and neuropeptide Y2 receptors

Cited by 13 publications

References 150 publications

A Peptide Triple Agonist of GLP-1, Neuropeptide Y1, and Neuropeptide Y2 Receptors Promotes Glycemic Control and Weight Loss

A Peptide Triple Agonist of GLP-1, Neuropeptide Y1, and Neuropeptide Y2 Receptors Promotes Glycemic Control and Weight Loss

The Genetic Basis of Future Pharmacological Strategies for the Management of Comorbid Obesity and Depression: A Scoping Review

Potentials of Neuropeptides as Therapeutic Agents for Neurological Diseases

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