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2.
PLoS One ; 14(6): e0217883, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31163066

RESUMO

PURPOSE: Melanocortin receptor 1 (MC1R) is overexpressed in melanoma and may be a molecular target for imaging and peptide receptor radionuclide therapy. 68Gallium (68Ga) labeling of DOTA-conjugated peptides is an established procedure in the clinic for use in positron emission tomography (PET) imaging. Aim of this study was to compare a standard labeling protocol against the 68Ga-DOTA peptide purified from the excess of unlabeled peptide. PROCEDURES: The MC1R ligand DOTA-NAPamide was labeled with 68Ga using a standard clinical protocol. Radioactive peptide was separated from the excess of unlabeled DOTA-NAPamide by HPLC. Immediately after the incubation of peptide and 68Ga (95°C, 15 min), the reaction was loaded on a C18 column and separated by a water/acetonitrile gradient, allowing fractionation in less than 20 minutes. Radiolabeled products were compared in biodistribution studies and PET imaging using nude mice bearing MC1R-expressing B16/F1 xenograft tumors. RESULTS: In biodistribution studies, non-purified 68Ga-DOTA-NAPamide did not show significant uptake in the tumor at 1 h post injection (0.78% IA/g). By the additional HPLC step, the molar activity was raised around 10,000-fold by completely removing unlabeled peptide. Application of this rapid purification strategy led to a more than 8-fold increase in tumor uptake (7.0% IA/g). The addition of various amounts of unlabeled DOTA-NAPamide to the purified product led to a blocking effect and decreased specific tumor uptake, similar to the result seen with non-purified radiopeptide. PET imaging was performed using the same tracer preparations. Purified 68Ga-DOTA-NAPamide, in comparison, showed superior tumor uptake. CONCLUSIONS: We demonstrated that chromatographic separation of radiolabeled from excess unlabeled peptide is technically feasible and beneficial, even for short-lived isotopes such as 68Ga. Unlabeled peptide molecules compete with receptor binding sites in the target tissue. Purification of the radiopeptide therefore improved tumor uptake.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Melanoma Experimental/metabolismo , Compostos Organometálicos/química , Fragmentos de Peptídeos/química , Ensaios Antitumorais Modelo de Xenoenxerto , alfa-MSH/análogos & derivados , Animais , Cromatografia de Fase Reversa , Cinética , Camundongos , Compostos Organometálicos/farmacocinética , Receptor Tipo 1 de Melanocortina/metabolismo , Distribuição Tecidual , alfa-MSH/química , alfa-MSH/farmacocinética
3.
Am J Clin Dermatol ; 20(5): 669-682, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31119650

RESUMO

Eruptive melanocytic nevi (EMN) is a phenomenon characterized by the sudden onset of nevi. Our objective was to compile all published reports of EMN to identify possible precipitating factors and to evaluate the clinical appearance and course. We conducted a systematic bibliographic search and selected 93 articles, representing 179 patients with EMN. The suspected causes were skin and other diseases (50%); immunosuppressive agents, chemotherapy or melanotan (41%); and miscellaneous, including idiopathic (9%). The clinical manifestations could largely be divided into two categories: EMN associated with skin diseases were frequently few in number (fewer than ten nevi), large, and localized to the site of previous skin disease, whereas those due to other causes presented most often with multiple small widespread nevi. In general, EMN seem to persist unchanged after their appearance, but development over several years or fading has also been reported. Overall, 16% of the cases had at least one histologically confirmed dysplastic nevus. Five cases of associated melanoma were reported. We conclude that the clinical appearance of EMN may differ according to the suggested triggering factor. Based on the clinical distinction, we propose a new subclassification of EMN: (1) widespread eruptive nevi (WEN), with numerous small nevi, triggered by, for example, drugs and internal diseases, and (2) Köbner-like eruptive nevi, often with big and few nevi, associated with skin diseases and most often localized at the site of previous skin disease/trauma. The nature of the data precluded assessment of risk of malignant transformation.


Assuntos
Síndrome do Nevo Displásico/epidemiologia , Nevo Pigmentado/epidemiologia , Neoplasias Cutâneas/epidemiologia , Síndrome do Nevo Displásico/diagnóstico , Síndrome do Nevo Displásico/etiologia , Humanos , Imunossupressores/efeitos adversos , Nevo Pigmentado/diagnóstico , Nevo Pigmentado/etiologia , Peptídeos Cíclicos/efeitos adversos , Fatores Desencadeantes , Medição de Risco , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/etiologia , alfa-MSH/efeitos adversos , alfa-MSH/análogos & derivados
4.
Molecules ; 24(10)2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31100979

RESUMO

In this work we summarize our understanding of melanocortin 4 receptor (MC4R) pathway activation, aiming to define a safe and effective therapeutic targeting strategy for the MC4R. Delineation of cellular MC4R pathways has provided evidence for distinct MC4R signaling events characterized by unique receptor activation kinetics. While these studies remain narrow in scope, and have largely been explored with peptidic agonists, the results provide a possible correlation between distinct ligand groups and differential MC4R activation kinetics. In addition, when a set of small-molecule and peptide MC4R agonists are compared, evidence of biased signaling has been reported. The results of such mechanistic studies are discussed.


Assuntos
Peptídeos/farmacocinética , Receptor Tipo 4 de Melanocortina/agonistas , Receptor Tipo 4 de Melanocortina/metabolismo , Transdução de Sinais , Animais , Peso Corporal , Sistema Cardiovascular/efeitos dos fármacos , AMP Cíclico/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Humanos , Cinética , Ligantes , Peptídeos/química , Peptídeos/farmacologia , Primatas , Ligação Proteica , Transporte Proteico , Roedores , Transdução de Sinais/efeitos dos fármacos , alfa-MSH/análogos & derivados , alfa-MSH/farmacologia
5.
Dermatol Clin ; 37(2): 175-181, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30850040

RESUMO

Pigmentary disorders are common and can be very distressing to patients. There is a need for better, standardized therapies. The authors review the most recent data for topical, systemic, light, and laser treatments for vitiligo, melasma, and postinflammatory hyperpigmentation. There is a paucity of large-scale, well-designed, randomized, controlled trials for these treatments. Treatment options are often drawn from smaller trials and case series. The treatments described in this article are promising candidates for larger follow-up studies.


Assuntos
Fármacos Dermatológicos/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Transtornos da Pigmentação/terapia , Antifibrinolíticos/uso terapêutico , Bimatoprost/uso terapêutico , Humanos , Hidroquinonas/uso terapêutico , Inflamação , Queratinócitos/transplante , Lasers de Estado Sólido/uso terapêutico , Terapia com Luz de Baixa Intensidade , Melanócitos/transplante , Melanose , Preparações Clareadoras de Pele/uso terapêutico , Protetores Solares/uso terapêutico , Ácido Tranexâmico/uso terapêutico , Vitiligo/terapia , alfa-MSH/análogos & derivados , alfa-MSH/uso terapêutico
6.
PLoS One ; 14(3): e0213397, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30901323

RESUMO

BACKGROUND: Although a 3-arm DOTA construct, which has three carboxylic acids, h has been applied for conjugation to many peptides, we investigated if a 4-arm DOTA construct conjugated to peptides improves chemical properties for melanoma imaging of the melanocortin 1 receptor compared to 3-arm DOTA-conjugated peptides. METHODS: Specific activities, radiolabeling efficiencies, and partition coefficients were evaluated using 111In-labeled 3-arm and 4-arm DOTA-α-melanocyte-stimulating hormone (MSH). For assessment of MC1-R affinity and accumulation in tumor cells in vitro, B16-F1 melanoma and/or 4T1 breast cancer cells were incubated with 111In-labeled 3-arm and 4-arm DOTA-α-MSH with and without α-MSH as a substrate. The stability was evaluated using mouse liver homogenates and plasma. Biological distribution and whole-body single photon emission computed tomography imaging of 111In-labeled 3-arm and 4-arm DOTA-α-MSH were obtained using B16-F1 melanoma-bearing mice. RESULTS: Specific activities and radiolabeling efficiencies of both radiotracers were about 1.2 MBq/nM and 90-95%, respectively. The partition coefficients were -0.28 ± 0.03 for 111In-labeled 3-arm DOTA-α-MSH and -0.13 ± 0.04 for 111In-labeled 4-arm DOTA-α-MSH. Although accumulation was significantly inhibited by α-MSH in B16-F1 cells, the inhibition rate of 111In-labeled 4-arm DOTA-α-MSH was lower than that of 111In-labeled 3-arm DOTA-α-MSH. 111In-labeled 4-arm DOTA-α-MSH was taken up early into B16-F1 cells and showed higher accumulation than 111In-labeled 3-arm DOTA-α-MSH after 10 min of incubation. Although these stabilities were relatively high, the stability of 111In-labeled 4-arm DOTA-α-MSH was higher than that of 111In-labeled 3-arm DOTA-α-MSH. Regarding biological distribution, 111In-labeled 4-arm DOTA-α-MSH showed significantly lower average renal accumulation (1.38-fold) and significantly higher average melanoma accumulation (1.32-fold) than 111In-labeled 3-arm DOTA-α-MSH at all acquisition times. 111In-labeled 4-arm DOTA-α-MSH showed significantly higher melanoma-to-kidney, melanoma-to-blood, and melanoma-to-muscle ratios than 111In-labeled 3-arm DOTA-α-MSH. CONCLUSIONS: The 4-arm DOTA construct has better chemical properties for peptide radiotracers than the 3-arm DOTA construct.


Assuntos
Complexos de Coordenação , Compostos Heterocíclicos com 1 Anel , Melanoma Experimental/diagnóstico por imagem , Compostos Radiofarmacêuticos , alfa-MSH/análogos & derivados , Animais , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Estabilidade de Medicamentos , Feminino , Compostos Heterocíclicos com 1 Anel/síntese química , Compostos Heterocíclicos com 1 Anel/química , Radioisótopos de Índio , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Tomografia Computadorizada de Emissão de Fóton Único , alfa-MSH/química
7.
BMJ Case Rep ; 12(2)2019 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-30796078

RESUMO

Melanocortin analogues, such as melanotan, are illegally used for artificial tanning. They have also been suggested as possible therapeutic agents in the treatment of erectile dysfunction. This case study presents a patient attending the accident and emergency department, in a tertiary urology centre, with acute priapism after abdominal subcutaneous injection of melanotan. The priapism was diagnosed as 'low-flow' and managed with cavernosal aspiration, irrigation and subsequent intracavernosal injection of phenylephrine. The patient avoided requiring surgical shunting but had not yet recovered erectile function at 4-week follow-up. Acute priapism is an unreported side effect of melanocortin analogue use and this case report presents a patient managed without surgical intervention. Future therapeutic application of these agents will need to take this potential life altering complication into consideration.


Assuntos
Melanocortinas/efeitos adversos , Pênis/efeitos dos fármacos , Peptídeos Cíclicos/efeitos adversos , Fármacos Fotossensibilizantes/efeitos adversos , Priapismo/induzido quimicamente , Recuperação de Função Fisiológica/efeitos dos fármacos , alfa-MSH/análogos & derivados , Adulto , Humanos , Masculino , Melanocortinas/farmacologia , Pênis/fisiopatologia , Peptídeos Cíclicos/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Recuperação de Função Fisiológica/fisiologia , Bronzeado , Fatores de Tempo , alfa-MSH/efeitos adversos , alfa-MSH/farmacologia
8.
PLoS One ; 14(1): e0210389, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30629642

RESUMO

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impaired social interactions, difficulty with communication, and repetitive behavior patterns. In humans affected by ASD, there is a male pre-disposition towards the condition with a male to female ratio of 4:1. In part due to the complex etiology of ASD including genetic and environmental interplay, there are currently no available medical therapies to improve the social deficits of ASD. Studies in rodent models and humans have shown promising therapeutic effects of oxytocin in modulating social adaptation. One pharmacological approach to stimulating oxytocinergic activity is the melanocortin receptor 4 agonist Melanotan-II (MT-II). Notably the effects of oxytocin on environmental rodent autism models has not been investigated to date. We used a maternal immune activation (MIA) mouse model of autism to assess the therapeutic potential of MT-II on autism-like features in adult male mice. The male MIA mice exhibited autism-like features including impaired social behavioral metrics, diminished vocal communication, and increased repetitive behaviors. Continuous administration of MT-II to male MIA mice over a seven-day course resulted in rescue of social behavioral metrics. Normal background C57 male mice treated with MT-II showed no significant alteration in social behavioral metrics. Additionally, there was no change in anxiety-like or repetitive behaviors following MT-II treatment of normal C57 mice, though there was significant weight loss following subacute treatment. These data demonstrate MT-II as an effective agent for improving autism-like behavioral deficits in the adult male MIA mouse model of autism.


Assuntos
Transtorno Autístico/tratamento farmacológico , Peptídeos Cíclicos/uso terapêutico , alfa-MSH/análogos & derivados , Animais , Comportamento Animal/efeitos dos fármacos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor Tipo 4 de Melanocortina/metabolismo , Receptor Tipo 4 de Melanocortina/fisiologia , Comportamento Social , alfa-MSH/uso terapêutico
9.
Dermatol Online J ; 24(5)2018 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30142729

RESUMO

Melanotan-I and melanotan-II are alpha-melanocyte stimulating hormone (a-MSH) analogues that can be purchased illicitly online with relative ease and are injected subcutaneously to stimulate a tan. Little is known about the use of these unregulated substances. An observational survey was posted to an online forum in which participants share their experiences using melanotan-I or melanotan-II. Users were asked to complete this voluntary, anonymous survey, which had questions focusing on motivation and hesitation for and against using melanotan, difficulty in acquiring it, and plans for continuing to use melanotan in the future.


Assuntos
Tráfico de Drogas , Peptídeos Cíclicos , Pigmentação da Pele/efeitos dos fármacos , alfa-MSH/análogos & derivados , Adolescente , Adulto , Indústria da Beleza , Tráfico de Drogas/psicologia , Feminino , Humanos , Hiperpigmentação/induzido quimicamente , Injeções Subcutâneas , Internacionalidade , Internet , Masculino , Pessoa de Meia-Idade , Peptídeos Cíclicos/administração & dosagem , Bronzeado/efeitos dos fármacos , Inquéritos e Questionários , Adulto Jovem , alfa-MSH/administração & dosagem
10.
Am J Physiol Regul Integr Comp Physiol ; 315(4): R751-R758, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30024775

RESUMO

Reducing body weight has been shown to lower blood pressure in obesity-related hypertension. However, success of those lifestyle interventions is limited due to poor long-term compliance. Emerging evidence indicates that feeding schedule plays a role on the regulation of blood pressure. With two studies, we examined the role of feeding schedule on energy homeostasis and blood pressure. In study 1, rats were fed a high-fat diet (HFD) ad libitum for 24 h (Control) or for 12 h during the dark phase (time-restricted feeding, TRF). In study 2, rats fed a HFD were administered a long-acting α-MSH analog at either light onset [melanotan II (MTII) light] or dark onset (MTII dark) or saline (Control). MTII light animals ate most of their calories during the active phase, similar to the TRF group. In study 1, Control and TRF rats consumed the same amount of food and gained the same amount of weight and fat mass. Interestingly, systolic and mean arterial pressure (MAP) was lower in the TRF group. In study 2, food intake was significantly lower in both MTII groups relative to Control. Although timing of injection affected light versus dark phase food consumption, neither body weight nor fat mass differed between MTII groups. Consistent with study 1, rats consuming their calories during the active phase displayed lower MAP. These data indicate that limiting feeding to the active phase reduces blood pressure without the necessity of reducing calories or fat mass, which could be relevant to obesity-related hypertension.


Assuntos
Ciclos de Atividade , Pressão Arterial/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Jejum , Hipertensão/dietoterapia , Obesidade/dietoterapia , Peptídeos Cíclicos/administração & dosagem , alfa-MSH/análogos & derivados , Adiposidade/efeitos dos fármacos , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Ingestão de Energia , Comportamento Alimentar/efeitos dos fármacos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Obesidade/metabolismo , Obesidade/fisiopatologia , Fotoperíodo , Ratos Endogâmicos BN , Ratos Endogâmicos F344 , Fatores de Tempo , alfa-MSH/administração & dosagem
11.
J Clin Endocrinol Metab ; 103(7): 2601-2612, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29726959

RESUMO

Context: The hypothalamic melanocortin 4 receptor (MC4R) pathway serves a critical role in regulating body weight. Loss of function (LoF) mutations in the MC4R pathway, including mutations in the pro-opiomelanocortin (POMC), prohormone convertase 1 (PCSK1), leptin receptor (LEPR), or MC4R genes, have been shown to cause early-onset severe obesity. Methods: Through a comprehensive epidemiological analysis of known and predicted LoF variants in the POMC, PCSK1, and LEPR genes, we sought to estimate the number of US individuals with biallelic MC4R pathway LoF variants. Results: We predict ~650 α-melanocyte-stimulating hormone (MSH)/POMC, 8500 PCSK1, and 3600 LEPR homozygous and compound heterozygous individuals in the United States, cumulatively enumerating >12,800 MC4R pathway-deficient obese patients. Few of these variants have been genetically diagnosed to date. These estimates increase when we include a small subset of less rare variants: ß-MSH/POMC,PCSK1 N221D, and a PCSK1 LoF variant (T640A). To further define the MC4R pathway and its potential impact on obesity, we tested associations between body mass index (BMI) and LoF mutation burden in the POMC, PCSK1, and LEPR genes in various populations. We show that the cumulative allele burden in individuals with two or more LoF alleles in one or more genes in the MC4R pathway are predisposed to a higher BMI than noncarriers or heterozygous LoF carriers with a defect in only one gene. Conclusions: Our analysis represents a genetically rationalized study of the hypothalamic MC4R pathway aimed at genetic patient stratification to determine which obese subpopulations should be studied to elucidate MC4R agonist (e.g., setmelanotide) treatment responsiveness.


Assuntos
Mutação com Perda de Função/genética , Obesidade/epidemiologia , Obesidade/genética , Receptor Tipo 4 de Melanocortina/genética , Transdução de Sinais/genética , Alelos , Fármacos Antiobesidade/farmacologia , Índice de Massa Corporal , Feminino , Heterozigoto , Homozigoto , Humanos , Masculino , Obesidade/tratamento farmacológico , Pró-Opiomelanocortina/genética , Pró-Proteína Convertase 1/genética , Receptor Tipo 4 de Melanocortina/agonistas , Receptores para Leptina/genética , Estados Unidos/epidemiologia , alfa-MSH/análogos & derivados , alfa-MSH/farmacologia
12.
Mol Pharm ; 15(6): 2116-2122, 2018 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-29714486

RESUMO

Melanocortin 1 receptor (MC1R) is specifically expressed in the majority of melanomas, a leading cause of death related to skin cancers. Accurate staging and early detection is crucial in managing melanoma. Based on the α-melanocyte-stimulating hormone (αMSH) sequence, MC1R-targeted peptides have been studied for melanoma imaging, predominately for use with single-photon emission computed tomography, with few attempts made for positron emission tomography (PET). 18F is a commonly used PET isotope due to readily available cyclotron production, pure positron emission, and a favorable half-life (109.8 min). In this study, we aim to design and evaluate αMSH derivatives that enable radiolabeling with 18F for PET imaging of melanoma. We synthesized three imaging probes based on the structure of Nle4-cyclo[Asp5-His-d-Phe7-Arg-Trp-Lys10]-NH2 (Nle-CycMSHhex), with a Pip linker (CCZ01064), an Acp linker (CCZ01070), or an Aoc linker (CCZ01071). 18F labeling was enabled by an ammoniomethyl-trifluoroborate (AmBF3) moiety. In vitro competition binding assays showed subnanomolar inhibition constant ( Ki) values for all three peptides. The 18F radiolabeling was performed via a one-step 18F-19F isotope exchange reaction that resulted in high radiochemical purity (>95%) and good molar activity (specific activity) ranging from 40.7 to 66.6 MBq/nmol. All three 18F-labeled peptides produced excellent tumor visualization with PET imaging in C57BL/6J mice bearing B16-F10 tumors. The tumor uptake was 7.80 ± 1.77, 5.27 ± 2.38, and 5.46 ± 2.64% injected dose per gram of tissue (%ID/g) for [18F]CCZ01064, [18F]CCZ01070, and [18F]CCZ01071 at 1 h post-injection (p.i.), respectively. Minimal background activity was observed except for kidneys at 4.99 ± 0.20, 4.42 ± 0.54, and 13.55 ± 2.84%ID/g, respectively. The best candidate [18F]CCZ01064 was further evaluated at 2 h p.i., which showed increased tumor uptake at 11.96 ± 2.31%ID/g and further reduced normal tissue uptake. Moreover, a blocking study was performed for CCZ01064 at 1 h p.i., where tumor uptake was significantly reduced to 1.97 ± 0.60%ID/g, suggesting the tumor uptake was receptor mediated. In conclusion, [18F]CCZ01064 showed high tumor uptake, low normal tissue uptake, and fast clearance and is therefore a suitable and promising candidate for PET imaging of melanoma.


Assuntos
Melanoma Experimental/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/administração & dosagem , Neoplasias Cutâneas/diagnóstico por imagem , alfa-MSH/administração & dosagem , Animais , Linhagem Celular Tumoral/transplante , Radioisótopos de Flúor , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Imagem Molecular/métodos , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Receptor Tipo 1 de Melanocortina/metabolismo , Neoplasias Cutâneas/patologia , Distribuição Tecidual , alfa-MSH/análogos & derivados , alfa-MSH/química , alfa-MSH/farmacocinética
13.
Nat Med ; 24(5): 551-555, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29736023

RESUMO

Genetic defects underlying the melanocortin-4 receptor (MC4R) signaling pathway lead to severe obesity. Three severely obese LEPR-deficient individuals were administered the MC4R agonist setmelanotide, resulting in substantial and durable reductions in hyperphagia and body weight over an observation period of 45-61 weeks. Compared to formerly developed and tested MC4R agonists, setmelanotide has the unique capability of activating nuclear factor of activated T cell (NFAT) signaling and restoring function of this signaling pathway for selected MC4R variants. Our data demonstrate the potency of setmelanotide in treatment of individuals with diverse MC4R-related pathway deficiencies.


Assuntos
Receptor Tipo 4 de Melanocortina/agonistas , Receptores para Leptina/deficiência , Perda de Peso , Adolescente , Ativação Enzimática/efeitos dos fármacos , Células HEK293 , Humanos , Masculino , Peptídeos/farmacologia , Receptores para Leptina/genética , Fosfolipases Tipo C/metabolismo , Perda de Peso/efeitos dos fármacos , Adulto Jovem , alfa-MSH/análogos & derivados , alfa-MSH/farmacologia
14.
Am J Physiol Endocrinol Metab ; 315(3): E357-E366, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29812984

RESUMO

Intraperitoneal administration of the melanocortin agonist melanotan II (MTII) to mice causes a profound, transient hypometabolism/hypothermia. It is preserved in mice lacking any one of melanocortin receptors 1, 3, 4, or 5, suggesting a mechanism independent of the canonical melanocortin receptors. Here we show that MTII-induced hypothermia was abolished in KitW-sh/W-sh mice, which lack mast cells, demonstrating that mast cells are required. MRGPRB2 is a receptor that detects many cationic molecules and activates mast cells in an antigen-independent manner. In vitro, MTII stimulated mast cells by both MRGPRB2-dependent and -independent mechanisms, and MTII-induced hypothermia was intact in MRGPRB2-null mice. Confirming that MTII activated mast cells, MTII treatment increased plasma histamine levels in both wild-type and MRGPRB2-null, but not in KitW-sh/W-sh, mice. The released histamine produced hypothermia via histamine H1 receptors because either a selective antagonist, pyrilamine, or ablation of H1 receptors greatly diminished the hypothermia. Other drugs, including compound 48/80, a commonly used mast cell activator, also produced hypothermia by both mast cell-dependent and -independent mechanisms. These results suggest that mast cell activation should be considered when investigating the mechanism of drug-induced hypothermia in mice.


Assuntos
Agonistas dos Receptores Histamínicos/farmacologia , Hipotermia/induzido quimicamente , Mastócitos/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , alfa-MSH/análogos & derivados , Animais , Liberação de Histamina/efeitos dos fármacos , Liberação de Histamina/genética , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , alfa-MSH/farmacologia
15.
ChemMedChem ; 13(11): 1146-1158, 2018 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-29659163

RESUMO

α-Melanocyte stimulating hormone (α-MSH) derivatives target the melanocortin-1 receptor (MC1R) specifically and selectively. In this study, the α-MSH-derived peptide NAP-NS1 (Nle-Asp-His-d-Phe-Arg-Trp-Gly-NH2 ) with and without linkers was conjugated with 5-(bis(pyridin-2-ylmethyl)amino)pentanoic acid (DPA-COOH) and labeled with [99m Tc]Tc-tricarbonyl by two methods. With the one-pot method the labeling was faster than with the two-pot method, while obtaining similarly high yields. Negligible trans-chelation and high stability in physiological solutions was determined for the [99m Tc]Tc-tricarbonyl-peptide conjugates. Coupling an ethylene glycol (EG)-based linker increased the hydrophilicity. The peptide derivatives displayed high binding affinity in murine B16F10 melanoma cells as well as in human MeWo and TXM13 melanoma cell homogenates. Preliminary in vivo studies with one of the [99m Tc]Tc-tricarbonyl-peptide conjugates showed good stability in blood and both renal and hepatobiliary excretion. Biodistribution was performed on healthy rats to gain initial insight into the potential relevance of the 99m Tc-labeled peptides for in vivo imaging.


Assuntos
Melanoma/diagnóstico por imagem , Compostos de Organotecnécio/farmacologia , Piridinas/farmacologia , Compostos Radiofarmacêuticos/farmacologia , alfa-MSH/análogos & derivados , alfa-MSH/farmacologia , Animais , Linhagem Celular Tumoral , Estabilidade de Medicamentos , Humanos , Masculino , Camundongos , Compostos de Organotecnécio/síntese química , Compostos de Organotecnécio/metabolismo , Piridinas/síntese química , Piridinas/metabolismo , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/metabolismo , Ratos Wistar , Tecnécio/química , Distribuição Tecidual , alfa-MSH/síntese química , alfa-MSH/metabolismo
16.
Am J Physiol Regul Integr Comp Physiol ; 314(4): R533-R539, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29351428

RESUMO

Although central melanocortin 4 receptor (MC4R) blockade abolishes the central nervous system (CNS)-mediated anorexogenic, antidiabetic, and cardiovascular actions of leptin, chronic MC4R stimulation fails to completely mimic the effects of leptin. Because neuropeptide Y (NPY) and MC4R exert opposite effects on cardiovascular and metabolic functions, we tested the role of NPY in offsetting the long-term actions of MC4R activation. Wild-type (WT) and NPY-deficient (NPY-/-) mice were implanted with telemetry probes for measuring mean arterial pressure (MAP) and heart rate (HR) 24 h/day. After the mice recovered from surgery and stable baseline measurements, the MC3/4R agonist melanotan II (MTII, 120 µg·kg-1·day-1 iv) was infused for 7 days followed by a recovery period. No major differences between groups were observed at baseline except for slightly higher food intake and HR in NPY-/- mice (4.3 ± 0.2 vs. 3.4 ± 0.2 g/day and 567 ± 14 vs. 522 ± 13 beats/min). Chronic MTII infusion reduced food intake in both groups while causing transient increases in MAP and HR only in WT mice (peaks of 11 ± 3 mmHg and 126 ± 13 beats/min). To examine whether NPY deficiency would amplify the antidiabetic effects of MC4R activation, diabetes was induced with streptozotocin (STZ) 1 wk before baseline measurements were taken, and the same experimental protocol was followed. In WT and NPY-/- mice, STZ-induced diabetes led to similar hyperphagia, hyperglycemia, and weight loss, which were not reversed by chronic MTII treatment. Our results demonstrate that chronic MC4R activation, even in NPY-deficient mice, does not mimic chronic antidiabetic, cardiovascular, or metabolic actions of leptin, and that NPY is not essential for hyperphagia or cardiovascular changes associated with diabetes.


Assuntos
Depressores do Apetite/administração & dosagem , Regulação do Apetite/efeitos dos fármacos , Pressão Arterial/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Neuropeptídeo Y/deficiência , Peptídeos Cíclicos/administração & dosagem , Receptor Tipo 4 de Melanocortina/agonistas , alfa-MSH/análogos & derivados , Animais , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Experimental/psicologia , Frequência Cardíaca/efeitos dos fármacos , Infusões Intravenosas , Insulina/sangue , Leptina/sangue , Masculino , Camundongos Knockout , Neuropeptídeo Y/genética , Receptor Tipo 4 de Melanocortina/metabolismo , Transdução de Sinais/efeitos dos fármacos , alfa-MSH/administração & dosagem
17.
Can J Physiol Pharmacol ; 96(3): 308-312, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29131966

RESUMO

Recent evidence indicate that melanotan II (MTII) reduces body mass independently of caloric reduction. Because MTII induces a transient hypophagia, caloric reduction is still considered a primary mechanism for MTII-mediated body mass loss. To examine the contribution of caloric reduction to long-term body mass loss in response to MTII, we centrally infused MTII or vehicle in ad libitum fed (MTII and Control) animals in comparison with a group of animals that were pair-fed (PF) to the MTII group. Food intake and body mass were recorded daily, and body composition was assessed biweekly. The present study demonstrates that central MTII-mediated body mass loss is only partially mediated by caloric restriction, and the long-term body mass loss is independent of the initial hypophagia. More importantly, central MTII administration induced a rapid but sustained fat mass loss, independently of caloric reduction. MTII-treated animals preserved their lean/fat mass ratio throughout the study, whereas PF animals underwent a transient reduction of lean/fat mass ratio that was only normalized when food intake returned to Control level. In summary, it can be concluded that activation of the central melanocortin system in rats persistently reduces body and fat mass independently of caloric reduction.


Assuntos
Tecido Adiposo/citologia , Peso Corporal , Restrição Calórica , Melanocortinas/metabolismo , Tecido Adiposo/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Masculino , Peptídeos Cíclicos/farmacologia , Ratos , alfa-MSH/análogos & derivados , alfa-MSH/farmacologia
18.
ACS Chem Neurosci ; 9(2): 320-327, 2018 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-28968061

RESUMO

Central administration of melanocortin ligands has been used as a critical technique to study energy homeostasis. While intracerebroventricular (ICV) injection is the most commonly used method during these investigations, intrathecal (IT) injection can be equally efficacious for the central delivery of ligands. Importantly, intrathecal administration can optimize exploration of melanocortin receptors in the spinal cord. Herein, we investigate comparative IT and ICV administration of two melanocortin ligands, the synthetic MTII (Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2) MC4R agonist and agouti-related peptide [AGRP(87-132)] MC4R inverse agonist/antagonist, on the same batch of age-matched mice in TSE metabolic cages undergoing a nocturnal satiated paradigm. To our knowledge, this is the first study to test how central administration of these ligands directly to the spinal cord affects energy homeostasis. Results showed, as expected, that MTII IT administration caused a decrease in food and water intake and an overall negative energy balance without affecting activity. As anticipated, IT administration of AGRP caused weight gain, increase of food/water intake, and increase respiratory exchange ratio (RER). Unexpectantly, the prolonged activity of AGRP was notably shorter (2 days) compared to mice given ICV injections of the same concentrations in previous studies (7 days or more).1-4 It appears that IT administration results in a more sensitive response that may be a good approach for testing synthetic compound potency values ranging in nanomolar to high micromolar in vitro EC50 values. Indeed, our investigation reveals that the spine influences a different melanocortin response compared to the brain for the AGRP ligand. This study indicates that IT administration can be a useful technique for future metabolic studies using melanocortin ligands and highlights the importance of exploring the role of melanocortin receptors in the spinal cord.


Assuntos
Proteína Relacionada com Agouti/administração & dosagem , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Fragmentos de Peptídeos/administração & dosagem , Receptor Tipo 4 de Melanocortina/agonistas , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , alfa-MSH/análogos & derivados , Animais , Cateteres de Demora , Estudos Cross-Over , Injeções Intraventriculares , Injeções Espinhais , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Receptor Tipo 4 de Melanocortina/metabolismo , Fatores de Tempo , alfa-MSH/administração & dosagem
19.
Mol Imaging ; 16: 1536012117737919, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29182034

RESUMO

Melanoma is a deadly disease at late metastatic stage, and early diagnosis and accurate staging remain the key aspects for managing melanoma. The melanocortin 1 receptor (MC1 R) is overexpressed in primary and metastatic melanomas, and its endogenous ligand, the α-melanocyte-stimulating hormone (αMSH), has been extensively studied for the development of MC1 R-targeted molecular imaging and therapy of melanoma. Natural αMSH is not well suited for this purpose due to low stability in vivo. Unnatural amino acid substitutions substantially stabilized the peptide, while cyclization via lactam bridge and metal coordination further improved binding affinity and stability. In this study, we summarized the development and the in vitro and in vivo characteristics of the radiolabeled αMSH analogues, including 99mTc-, 111In-, 67 Ga-, or 125I-labeled αMSH analogues for imaging with single-photon emission computed tomography; 68Ga-, 64Cu-, or 18F-labeled αMSH analogues for imaging with positron emission tomography; and 188Re-, 177Lu-, 90Y-, or 212Pb-labeled αMSH analogues for radionuclide therapy. These radiolabeled αMSH analogues showed promising results with high tumor uptake and rapid normal tissue activity clearance in the preclinical model of B16F1 and B16F10 mouse melanomas. These results highlight the potential of using radiolabeled αMSH analogues in clinical applications for molecular imaging and radionuclide therapy of melanoma.


Assuntos
Melanoma/diagnóstico por imagem , Melanoma/tratamento farmacológico , Compostos Radiofarmacêuticos/uso terapêutico , Receptor Tipo 1 de Melanocortina/antagonistas & inibidores , alfa-MSH/análogos & derivados , Animais , Detecção Precoce de Câncer , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Melanoma/metabolismo , Imagem Molecular/métodos , Compostos Radiofarmacêuticos/farmacologia , Tomografia Computadorizada de Emissão de Fóton Único , Regulação para Cima/efeitos dos fármacos , alfa-MSH/química
20.
J Med Chem ; 60(22): 9320-9329, 2017 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-29094944

RESUMO

Melanoma is a lethal form of skin cancer. Skin pigmentation, which is regulated by the melanocortin 1 receptor (MC1R), is an effective protection against melanoma. However, the endogenous MC1R agonists lack selectivity for the MC1R and thus can have side effects. The use of noncanonical amino acids in previous MC1R ligand development raises safety concerns. Here we report the development of the first potent and selective hMC1R agonist with only canonical amino acids. Using γ-MSH as a template, we developed a peptide, [Leu3, Leu7, Phe8]-γ-MSH-NH2 (compound 5), which is 16-fold selective for the hMC1R (EC50 = 4.5 nM) versus other melanocortin receptors. Conformational studies revealed a constrained conformation for this linear peptide. Molecular docking demonstrated a hydrophobic binding pocket for the melanocortin 1 receptor. In vivo pigmentation study shows high potency and short duration. [Leu3, Leu7, Phe8]-γ-MSH-NH2 is ideal for inducing short-term skin pigmentation without sun for melanoma prevention.


Assuntos
Hormônios Hipotalâmicos/farmacologia , Hormônios Estimuladores de Melanócitos/farmacologia , Receptor Tipo 1 de Melanocortina/agonistas , Pigmentação da Pele/efeitos dos fármacos , Animais , Estabilidade de Medicamentos , Células HEK293 , Meia-Vida , Humanos , Hormônios Hipotalâmicos/administração & dosagem , Hormônios Hipotalâmicos/síntese química , Hormônios Hipotalâmicos/farmacocinética , Radioisótopos do Iodo , Ligantes , Hormônios Estimuladores de Melanócitos/administração & dosagem , Hormônios Estimuladores de Melanócitos/síntese química , Hormônios Estimuladores de Melanócitos/farmacocinética , Conformação Molecular , Simulação de Acoplamento Molecular , Receptor Tipo 1 de Melanocortina/química , Répteis , alfa-MSH/administração & dosagem , alfa-MSH/análogos & derivados , alfa-MSH/síntese química , alfa-MSH/farmacocinética , alfa-MSH/farmacologia
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