Aryl piperazine melanocortin MC4 receptor agonists

Dyck, Brian; Parker, Jessica; Phillips, Teresa A.; Carter, Lee; Murphy, Brian J.; Summers, Robin; Hermann, Julia; Baker, Tracy J.; Cismowski, Mary J.; Saunders, John; Goodfellow, Val S.

doi:10.1016/s0960-894x(03)00796-0

Cited by 44 publications

(16 citation statements)

References 10 publications

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“…Melanocortin selective agonists would be of a great interest in treating obese individuals or regulating skin pigmentation, while the discovery of the centrally selective MCR antagonists in treating cachexia and involuntary weight loss as a result of cancer would also be noteworthy. Initial piperazine based analogues attached to the DTic‐(p‐Cl)DPhe dipeptide resulted in the potent and selective MC4R analogues in the n m range (30). Additionally, similar piperazine and piperidine‐based melanocortin analogues have been reported (31–33).…”

Section: Discussionmentioning

confidence: 99%

“…The important physiological implications of the melanocortin system in the regulation of obesity and energy homeostasis have resulted in the discovery of small molecule ligands. Several publications have revealed the synthesis and pharmacological characterization of small molecule melanocortin ligands (based on the piperidine and piperazine scaffolds) (30–34) that may be related to the privileged structure and drug design approach. A privileged structure can be defined as the series of molecules with capacity to bind to multiple receptors with high affinity (35).…”

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confidence: 99%

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Structure–Activity Relationships of Melanocortin Agonists Containing the Benzimidazole Scaffold

et al. 2007

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The melanocortin system has been implicated in regulating various physiological processes including pigmentation, energy homeostasis, obesity, steroidogenesis cardiovascular, and exocrine gland function. The five melanocortin receptors that belong to the super family of G protein-coupled receptors are stimulated by naturally occurring agonists. The aim of this research was focused on the design, synthesis, and pharmacological characterization of melanocortin ligands that contain the 1,2,5-trisubstituted benzimidazole scaffold. A series of benzimidazole analogues, with three points of diversity at positions 1, 2, and 5, were designed, synthesized, pharmacologically assayed at the mouse melanocortin receptors MC1R, MC3R, MC4R, and MC5R and resulted in ligands possessing a range of agonist activity from nm to no stimulation at up to 100 microM concentrations. This study demonstrates that the benzimidazole structure template can be appended with key melanocortin agonist amino acids for the design melanocortin receptor agonist ligands.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Structure–Activity Relationships of Melanocortin Agonists Containing the Benzimidazole Scaffold

et al. 2007

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“…The first entry in this area came from Dyck and co-workers at Neurocrine Biosciences [25]. Analysis of the published literature and a screen of privileged structures identified compound 15 (Fig.…”

Section: (I) Privileged Structure Sarmentioning

confidence: 99%

Small Molecule Ligands of the Human Melanocortin-4 Receptor

Ujjainwalla¹,

Sebhat

2007

CTMC

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Genetic and pharmacological studies, involving both animals and humans, suggest that the central MC4 receptor plays a key role in homeostatic control, most probably via regulation of appetite and energy expenditure. This has stimulated intense research efforts in the field of drug discovery to identify MC4 receptor agonists and antagonists for the therapeutic treatment of obesity and diseases associated with loss of body weight. This article constitutes a near comprehensive review of the published scientific literature on small molecule ligands of the hMC4 receptor since 2002.

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“…The material in this section will not attempt to cover the subject matter of the past reviews or to survey the growing body of nearly 100 patents/applications in the MC4R agonist/ligand arena. Following these reports, Dyck and colleagues reported that 20 induced short term inhibition of food intake in fasted mice following intracerebroventricular (icv) administration [84]. Additionally, an attempt will be made to capture the compounds reported in the literature with either demonstrated exposure after oral administration or reported efficacy in models of food consumption.…”

Section: Small Molecules Hemi-peptides and Non-peptidesmentioning

confidence: 99%

Melanocortin - 4 Receptor Agonists for the Treatment of Obesity

Fisher¹,

Yan²,

Mayer

et al. 2007

CTMC

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The melanocortin family of receptors (MC 1-5R) and their endogenous peptide ligands (alpha, beta, gamma- MSH and ACTH) have been implicated in the control of a wide variety of behavioral and physiological functions including the homeostatic control of food intake and body weight. In rodent models, melanocortin agonists including the nonselective peptide MTII have been shown to decrease food intake and body weight while antagonists such as SHU9119 and AGRP have been shown to stimulate food intake and increase body weight. Deletion of either the MC3R or MC4R in mice was found to be associated with obesity although hyperphagia was only observed in the MC4R deficient mice. Similarly in humans, inactivating mutations of the MC4R have been found in as many as six percent of obese individuals. The suggestion from these findings that activation of MC4Rs would have an anorectic effect in humans has resulted in efforts to produce selective agonists for the treatment of obesity. Over the past decade, efforts to develop MC4R selective small molecule and peptide agonists have been met with fractional success. Many small molecule agonists have been identified; however, few have been shown to have activity in vivo. While their use as therapeutics may have limitations, selective and potent peptide agonists have been shown by several investigators to decrease food intake and body weight in rodent models. The subject of the current review is to examine the progress made to date on producing both small molecule and peptide MC4R agonists as potential therapeutics for obesity.

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Aryl piperazine melanocortin MC4 receptor agonists

Cited by 44 publications

References 10 publications

Structure–Activity Relationships of Melanocortin Agonists Containing the Benzimidazole Scaffold

Structure–Activity Relationships of Melanocortin Agonists Containing the Benzimidazole Scaffold

Small Molecule Ligands of the Human Melanocortin-4 Receptor

Melanocortin - 4 Receptor Agonists for the Treatment of Obesity

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