Design of novel melanocortin receptor ligands: Multiple receptors, complex pharmacology, the challenge

Hruby, Victor J.; Cai, Minying; Cain, James P.; Nyberg, Joel; Trivedi, Dev

doi:10.1016/j.ejphar.2010.10.109

Cited by 18 publications

(35 citation statements)

References 32 publications

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“…Melanotan I (MTI) [Nle 4 ,D-Phe 7 ]α-MSH is a potent analog of α-MSH with activity at the MC1, MC3, MC4, and MC5 receptors and good in vivo stability and biodistribution, but poor blood-brain barrier permeability (Hruby et al, 2011). Melanotan II (MTII), Ac-Nle-c[Asp 5 ,DPhe 7 ,Lys 10 ]α-MSH-NH2, is of similar potency and promiscuity as MTI but enhanced in vivo stability (T 1/2 : 1-2 h) and blood-brain barrier permeability because of its cyclic structure (Cai et al, 2005).…”

Section: Melanocortin Receptor Agonistsmentioning

confidence: 99%

Melanocortin Receptor Agonists Facilitate Oxytocin-Dependent Partner Preference Formation in the Prairie Vole

Modi

Inoue

Barrett

et al. 2015

Neuropsychopharmacol

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The central melanocortin (MC) system has been widely studied for its effects on food intake and sexual behavior. However, the MC system, and more specifically the MC4 receptor (MC4R), also interacts with neurochemical systems that regulate socioemotional behaviors, including oxytocin (OT) and dopamine. In monogamous prairie voles, OT and dopamine interact to promote partner preference formation, a laboratory measure of an enduring social bond between mates. Here we investigated the effects of MC receptor activation on partner preference formation in prairie voles, as well as the interaction between the MC and OT systems during this process. Peripheral administration of the brain penetrant MC3/4R receptor peptide agonist, Melanotan II (MTII), and the highly selective, small-molecule MC4R agonist, Pf-446687, enhanced partner preference formation in the prairie vole, but not in the non-monogamous meadow vole. MTII-induced partner preferences were enduring, as they were present 1 week after drug manipulation. The prosocial effects of MCR agonists may be mediated, in part, through modulation of OT, as coadministration of an OT receptor antagonist prevented MTII-induced partner preferences. MTII also selectively activated hypothalamic OT neurons and potentiated central OT release. As OT has been shown to enhance some aspects of social cognition in humans, our data suggest that the MC4R may be a viable therapeutic target for enhancing social function in psychiatric disorders, including autism spectrum disorders and schizophrenia, potentially through activation of the OT system.

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Section: Melanocortin Receptor Agonistsmentioning

confidence: 99%

Melanocortin Receptor Agonists Facilitate Oxytocin-Dependent Partner Preference Formation in the Prairie Vole

Modi

Inoue

Barrett

et al. 2015

Neuropsychopharmacol

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“…The need for new radiopharmaceuticals able to diagnose tumor in the early stages is evident. Native a-MSH has an extremely short biological half-life because it is easily hydrolyzed by proteases and also the methionine residue in a-MSH can be oxidized [12]. Newer generation agents have been designed to enhance their potency toward MC1 receptor, including peptides with linear structures [13][14][15][16] and cyclic structures [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Development of a 99mTc-labeled lactam bridge-cyclized alpha-MSH derivative peptide as a possible single photon imaging agent for melanoma tumors

et al. 2015

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“…79-84 However, the response of obese volunteers to compounds targeting MC4Rs in the clinic has thus far been discouraging due to limited effectiveness and side effects on cardiovascular function. 85 MC4Rs are not, however, the only member of the melanocortin receptor family involved in metabolic homeostasis.…”

Section: The “Leptin-melanocortin” Pathway: a Canonical Pathway LImentioning

confidence: 99%

Melanocortin-3 Receptors and Metabolic Homeostasis

Begriche¹,

Girardet²,

McDonald³

et al. 2013

Progress in Molecular Biology and Translational Science

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Attenuated activity of the central nervous melanocortin system causes obesity and insulin resistance. Obese rodents treated with melanocortins exhibit improvements in obesity and metabolic homeostasis that are not mutually dependent, suggesting metabolic actions that are independent of weight changes. These responses are generally thought to involve G-protein-coupled receptors expressed in the brain. Melanocortin-4 receptors (MC4Rs) regulate satiety and autonomic nervous system and thyroid function. MC3Rs are expressed in hypothalamic and limbic regions involved in controlling ingestive behaviors and autonomic function. Mc3r−/− mice exhibit increased adiposity and an accelerated diet-induced obesity. While this phenotype is not dependent on hyperphagia, data on the regulation of food intake by MC3Rs are inconsistent. Recent investigations by our laboratory suggest a unique combination of behavioral and metabolic disorders in Mc3r−/− mice. MC3Rs are critical for the expression of the anticipatory response and metabolic homeostasis when food intake occurs outside the normal voluntary rhythms driven by photoperiod. Using a Cre-Lox strategy, we can now investigate MC3Rs expressed in different brain regions and organ systems in the periphery. While focusing on the functions of neural MC3Rs, early results suggest an additional layer of complexity with central and peripheral MC3Rs involved in the defense of body weight.

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Design of novel melanocortin receptor ligands: Multiple receptors, complex pharmacology, the challenge

Cited by 18 publications

References 32 publications

Melanocortin Receptor Agonists Facilitate Oxytocin-Dependent Partner Preference Formation in the Prairie Vole

Melanocortin Receptor Agonists Facilitate Oxytocin-Dependent Partner Preference Formation in the Prairie Vole

Development of a 99mTc-labeled lactam bridge-cyclized alpha-MSH derivative peptide as a possible single photon imaging agent for melanoma tumors

Melanocortin-3 Receptors and Metabolic Homeostasis

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