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[PMID]: 28109166 [Au] Autor: Gydesen S; Hjuler ST; Freving Z; Andreassen KV; Sonne N; Hellgren LI; Karsdal MA; Henriksen K [Ad] Endereço: Nordic Bioscience, Herlev, Denmark. [Ti] Título: A novel dual amylin and calcitonin receptor agonist, KBP-089, induces weight loss through a reduction in fat, but not lean mass, while improving food preference. [So] Source: Br J Pharmacol;174(7):591-602, 2017 Apr. [Is] ISSN: 1476-5381 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: BACKGROUND AND PURPOSE: Obesity and associated co-morbidities, such as type 2 diabetes and non-alcoholic fatty liver disease, are major health challenges. Hence, there is an important need to develop weight loss therapies with the ability to reduce the co-morbidities. EXPERIMENTAL APPROACH: The effect of the dual amylin and calcitonin receptor agonist (DACRA), KBP-089, on body weight, glucose homeostasis and fatty acid accumulation in liver and muscle tissue and on food preference was investigated. Furthermore, we elucidated weight-independent effects of KBP-089 using a weight-matched group. KEY RESULTS: Rats fed a high-fat diet were treated, s.c., with KBP-089 0.625, 1.25, 2.5 µg·kg or vehicle. KB-089 induced in a dose-dependent and sustained weight loss (~17% by 2.5 µg·kg ). Moreover, KBP-089 reduced fat depot size and reduced lipid accumulation in muscle and liver. In Zucker Diabetic Fatty rats, KBP-089 improved glucose homeostasis through improved insulin action. To obtain a weight-matched group, significantly less food was offered (9% less than in the KBP-089 group). Weight matching led to improved glucose homeostasis by reducing plasma insulin; however, these effect were inferior compared to those of KBP-089. In the food preference test, rats fed a normal diet obtained 74% of their calories from chocolate. KBP-089 reduced total caloric intake and induced a relative increase in chow consumption while drastically reducing chocolate consumption compared with vehicle. CONCLUSIONS AND IMPLICATIONS: The novel DACRA, KBP-089, induces a sustained weight loss, leading to improved metabolic parameters including food preference, and these are beyond those observed simply by diet-induced weight loss. [Mh] Termos MeSH primário: Tecido Adiposo/efeitos dos fármacos Adiposidade/efeitos dos fármacos Preferências Alimentares/efeitos dos fármacos Receptores da Calcitonina/agonistas Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas/metabolismo Perda de Peso/efeitos dos fármacos [Mh] Termos MeSH secundário: Agonistas dos Receptores da Amilina/farmacologia Animais Dieta Hiperlipídica Relação Dose-Resposta a Droga Glucose/metabolismo Homeostase/efeitos dos fármacos Masculino Tamanho da Partícula Ratos Ratos Sprague-Dawley Ratos Zucker Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Amylin Receptor Agonists); 0 (Receptors, Calcitonin); 0 (Receptors, Islet Amyloid Polypeptide); IY9XDZ35W2 (Glucose) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171106 [Lr] Data última revisão: 171106 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170122 [St] Status: MEDLINE [do] DOI: 10.1111/bph.13723

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[PMID]: 27296301 [Au] Autor: Hjuler ST; Gydesen S; Andreassen KV; Pedersen SL; Hellgren LI; Karsdal MA; Henriksen K [Ad] Endereço: Nordic Bioscience, Herlev, Denmark. [Ti] Título: The dual amylin- and calcitonin-receptor agonist KBP-042 increases insulin sensitivity and induces weight loss in rats with obesity. [So] Source: Obesity (Silver Spring);24(8):1712-22, 2016 Aug. [Is] ISSN: 1930-739X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: OBJECTIVE: In this study, KBP-042, a dual amylin- and calcitonin-receptor agonist, was investigated as a treatment of obesity and insulin resistance in five different doses (0.625 µg/kg-10 µg/kg) compared with saline-treated and pair-fed controls. METHODS: Rats with obesity received daily s.c. administrations for 56 days, and glucose tolerance was assessed after one acute injection, 3 weeks of treatment, and again after 7 weeks of treatment. To assess the effect on insulin sensitivity, rats received 5 µg/kg KBP-042 for 21 days before hyperinsulinemic-euglycemic clamp. RESULTS: KBP-042 induced a sustained weight loss of up to 20% without any significant weight reduction in the pair-fed groups. Decreases in adipose tissues and lipid deposition in the liver were observed, while plasma adiponectin was increased and plasma leptin levels were decreased. Acute administration of KBP-042 led to impaired glucose tolerance and increased plasma lactate, while this diabetogenic effect was reversed by chronic treatment. Finally, assessment of insulin sensitivity using the hyperinsulinemic-euglycemic clamp showed that KBP-042 increased the glucose infusion rate. CONCLUSIONS: The study indicates that KBP-042 combines two highly relevant features, namely weight loss and insulin sensitivity, and is thus an excellent candidate for chronic treatment of obesity and insulin resistance. [Mh] Termos MeSH primário: Agonistas dos Receptores da Amilina/farmacologia Calcitonina/análogos & derivados Resistência à Insulina Obesidade/tratamento farmacológico Perda de Peso/efeitos dos fármacos [Mh] Termos MeSH secundário: Administração Oral Animais Glicemia/efeitos dos fármacos Calcitonina/farmacologia Teste de Tolerância a Glucose Polipeptídeo Amiloide das Ilhotas Pancreáticas/farmacologia Masculino Ratos Ratos Sprague-Dawley [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Amylin Receptor Agonists); 0 (Blood Glucose); 0 (Islet Amyloid Polypeptide); 0 (KBP-042); 9007-12-9 (Calcitonin) [Em] Mês de entrada: 1706 [Cu] Atualização por classe: 170616 [Lr] Data última revisão: 170616 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160615 [St] Status: MEDLINE [do] DOI: 10.1002/oby.21563

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[PMID]: 27061187 [Au] Autor: Bower RL; Hay DL [Ad] Endereço: School of Biological Sciences and Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand. [Ti] Título: Amylin structure-function relationships and receptor pharmacology: implications for amylin mimetic drug development. [So] Source: Br J Pharmacol;173(12):1883-98, 2016 Jun. [Is] ISSN: 1476-5381 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Amylin is an important, but poorly understood, 37 amino acid glucoregulatory hormone with great potential to target metabolic diseases. A working example that the amylin system is one worth developing is the FDA-approved drug used in insulin-requiring diabetic patients, pramlintide. However, certain characteristics of pramlintide pharmacokinetics and formulation leave considerable room for further development of amylin-mimetic compounds. Given that amylin-mimetic drug design and development is an active area of research, surprisingly little is known about the structure/function relationships of amylin. This is largely due to the unfavourable aggregative and solubility properties of the native peptide sequence, which are further complicated by the composition of amylin receptors. These are complexes of the calcitonin receptor with receptor activity-modifying proteins. This review explores what is known of the structure-function relationships of amylin and provides insights that can be drawn from the closely related peptide, CGRP. We also describe how this information is aiding the development of more potent and stable amylin mimetics, including peptide hybrids. [Mh] Termos MeSH primário: Agonistas dos Receptores da Amilina/farmacologia Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas/metabolismo [Mh] Termos MeSH secundário: Agonistas dos Receptores da Amilina/química Animais Desenho de Drogas Seres Humanos Polipeptídeo Amiloide das Ilhotas Pancreáticas/química Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Amylin Receptor Agonists); 0 (Islet Amyloid Polypeptide); 0 (Receptors, Islet Amyloid Polypeptide) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171023 [Lr] Data última revisão: 171023 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160411 [St] Status: MEDLINE [do] DOI: 10.1111/bph.13496

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[PMID]: 26908506 [Au] Autor: Gydesen S; Andreassen KV; Hjuler ST; Christensen JM; Karsdal MA; Henriksen K [Ad] Endereço: Nordic Bioscience, Herlev, Denmark; and sgy@nordicbioscience.com. [Ti] Título: KBP-088, a novel DACRA with prolonged receptor activation, is superior to davalintide in terms of efficacy on body weight. [So] Source: Am J Physiol Endocrinol Metab;310(10):E821-7, 2016 May 15. [Is] ISSN: 1522-1555 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: This study aims to elucidate the mechanism behind the potent weight loss induced by dual amylin and calcitonin receptor agonists (DACRA) through comparison of the novel DACRA KBP-088 with the amylinomimetic davalintide with regard to in vitro receptor pharmacology and in vivo efficacy on food intake and body weight. KBP-088 and davalintide were tested for their ability to activate the amylin and calcitonin receptors as function of dose and time. Two doses of KBP-088 (1.67 and 5.0 µg/kg) were compared with similar davalintide doses in high-fat diet (HFD)-fed rats receiving subcutaneous dosing once daily for 62 days. Glucose tolerance was assessed after 3 and 7 wk of treatment. KBP-088 demonstrated activation of amylin and calcitonin receptors and prolonged receptor activation compared with davalintide as well as a potent reduction of acute food intake. KBP-088 transiently reduced food intake and induced and notably sustained a significant ∼16% vehicle-corrected weight loss without significant weight loss in the calorie-restricted control groups. Additionally, KBP-088 reduced white adipose tissues and adipocyte hypertrophy. Finally, KBP-088 alleviated hyperinsulinemia and improved oral glucose tolerance even with significantly lower insulin levels after 3 and 7 wk of treatment. KBP-088 is a potent amylin and calcitonin receptor agonist with prolonged receptor activation compared with davalintide. Moreover, KBP-088 induced and sustained significant weight loss and reduced overall adiposity and adipocyte hypertrophy in HFD rats. Finally, KBP-088 improved oral glucose tolerance and alleviated hyperinsulinemia, underscoring the potential of KBP-088 as an antiobesity agent with benefits on glucose control. [Mh] Termos MeSH primário: Adipócitos/efeitos dos fármacos Tecido Adiposo Branco/efeitos dos fármacos Adiposidade/efeitos dos fármacos Agonistas dos Receptores da Amilina/farmacologia Peso Corporal/efeitos dos fármacos Ingestão de Alimentos/efeitos dos fármacos Peptídeos/farmacologia Receptores da Calcitonina/agonistas [Mh] Termos MeSH secundário: Animais Dieta Hiperlipídica Teste de Tolerância a Glucose Hiperinsulinismo Hipertrofia Insulina/sangue Masculino Ratos Ratos Sprague-Dawley [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Amylin Receptor Agonists); 0 (Insulin); 0 (Peptides); 0 (Receptors, Calcitonin); 0 (davalintide) [Em] Mês de entrada: 1706 [Cu] Atualização por classe: 170606 [Lr] Data última revisão: 170606 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160225 [St] Status: MEDLINE [do] DOI: 10.1152/ajpendo.00514.2015

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[PMID]: 26778650 [Au] Autor: Khoshdel Z; Takhshid MA; Owji AA [Ad] Endereço: Department of Biochemistry, Shiraz University of Medical Sciences, Shiraz, Iran. [Ti] Título: Effects of intrathecal amylin on formalin-induced nociception and on cAMP accumulation in the rat embryonic spinal cells. [So] Source: Neuropeptides;57:95-100, 2016 Jun. [Is] ISSN: 1532-2785 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: Amylin (AMY) is a member of calcitonin family of peptides. In this study, the effects of intrathecal (i.t) injection of AMY on the inflammatory pain and on the cAMP accumulation in the rat spinal cells were investigated. By using AMY receptor antagonists, we also studied the pharmacology of AMY receptors in the spinal cells. Formalin model of inflammatory pain was induced by intraplantar injection of formalin. AMY (0.06250-2500pmol/rat) was administrated i.t 15min before the injection of formalin. Antagonists were injected i.t 10min before the injection of AMY and/or morphine. AMY reduced formalin-induced pain in a dose dependent mode. This effect was inhibited by the potent AMY antagonist, AC187 but not CGRP8-37. rAMY8-37, most commonly reported as a weak AMY antagonist, showed to be equally or more potent than AC187 in antagonizing the above effects. The opioid antagonist, naloxone, had no significant effects on AMY antinociceptive effects. Primary dissociated cell culture was used to investigate the effect of AMY on cAMP production and to characterize AMY receptors in the spinal cells. AMY moderately increases cAMP accumulation in the spinal cells with an EC50 value of 74.62nM. This effect was not affected by CGRP8-37 but was inhibited by AC187 and rAMY8-37 with pA2 values of 7.94 and 7.87 respectively. In conclusion, effects of AMY in reducing formalin induced pain and on the cAMP accumulation by spinal cells are mediated through undefined receptors. [Mh] Termos MeSH primário: Analgésicos/administração & dosagem AMP Cíclico/metabolismo Inflamação/metabolismo Polipeptídeo Amiloide das Ilhotas Pancreáticas/administração & dosagem Nociceptividade/efeitos dos fármacos Medula Espinal/efeitos dos fármacos Medula Espinal/metabolismo [Mh] Termos MeSH secundário: Agonistas dos Receptores da Amilina/administração & dosagem Analgésicos Opioides/administração & dosagem Animais Peptídeo Relacionado com Gene de Calcitonina/administração & dosagem Formaldeído Inflamação/induzido quimicamente Injeções Espinhais Polipeptídeo Amiloide das Ilhotas Pancreáticas/antagonistas & inibidores Masculino Morfina/administração & dosagem Naloxona/administração & dosagem Antagonistas de Entorpecentes/administração & dosagem Dor/induzido quimicamente Limiar da Dor/efeitos dos fármacos Fragmentos de Peptídeos/administração & dosagem Cultura Primária de Células Ratos Ratos Sprague-Dawley Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas/antagonistas & inibidores Medula Espinal/embriologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Amylin Receptor Agonists); 0 (Analgesics); 0 (Analgesics, Opioid); 0 (Islet Amyloid Polypeptide); 0 (Narcotic Antagonists); 0 (Peptide Fragments); 0 (Receptors, Islet Amyloid Polypeptide); 119911-68-1 (calcitonin gene-related peptide (8-37)); 161902-50-7 (AC 187); 1HG84L3525 (Formaldehyde); 36B82AMQ7N (Naloxone); 76I7G6D29C (Morphine); 83652-28-2 (Calcitonin Gene-Related Peptide); E0399OZS9N (Cyclic AMP) [Em] Mês de entrada: 1702 [Cu] Atualização por classe: 170207 [Lr] Data última revisão: 170207 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160119 [St] Status: MEDLINE

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[PMID]: 25035079 [Au] Autor: Mietlicki-Baase EG; Reiner DJ; Cone JJ; Olivos DR; McGrath LE; Zimmer DJ; Roitman MF; Hayes MR [Ad] Endereço: Translational Neuroscience Program, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. [Ti] Título: Amylin modulates the mesolimbic dopamine system to control energy balance. [So] Source: Neuropsychopharmacology;40(2):372-85, 2015 Jan. [Is] ISSN: 1740-634X [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Amylin acts in the CNS to reduce feeding and body weight. Recently, the ventral tegmental area (VTA), a mesolimbic nucleus important for food intake and reward, was identified as a site-of-action mediating the anorectic effects of amylin. However, the long-term physiological relevance and mechanisms mediating the intake-suppressive effects of VTA amylin receptor (AmyR) activation are unknown. Data show that the core component of the AmyR, the calcitonin receptor (CTR), is expressed on VTA dopamine (DA) neurons and that activation of VTA AmyRs reduces phasic DA in the nucleus accumbens core (NAcC). Suppression in NAcC DA mediates VTA amylin-induced hypophagia, as combined NAcC D1/D2 receptor agonists block the intake-suppressive effects of VTA AmyR activation. Knockdown of VTA CTR via adeno-associated virus short hairpin RNA resulted in hyperphagia and exacerbated body weight gain in rats maintained on high-fat diet. Collectively, these findings show that VTA AmyR signaling controls energy balance by modulating mesolimbic DA signaling. [Mh] Termos MeSH primário: Agonistas dos Receptores da Amilina/farmacologia Depressores do Apetite/farmacologia Dopamina/metabolismo Polipeptídeo Amiloide das Ilhotas Pancreáticas/farmacologia Neurônios/efeitos dos fármacos Área Tegmentar Ventral/efeitos dos fármacos [Mh] Termos MeSH secundário: Animais Dieta Hiperlipídica Ingestão de Alimentos/efeitos dos fármacos Ingestão de Alimentos/fisiologia Masculino Neurônios/metabolismo RNA Mensageiro/metabolismo Ratos Sprague-Dawley Receptores da Calcitonina/antagonistas & inibidores Receptores da Calcitonina/genética Receptores da Calcitonina/metabolismo Receptores de Dopamina D1/agonistas Receptores de Dopamina D1/metabolismo Receptores de Dopamina D2/agonistas Receptores de Dopamina D2/metabolismo Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas/metabolismo Área Tegmentar Ventral/metabolismo Ganho de Peso/efeitos dos fármacos Ganho de Peso/fisiologia [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL [Nm] Nome de substância: 0 (Amylin Receptor Agonists); 0 (Appetite Depressants); 0 (Islet Amyloid Polypeptide); 0 (RNA, Messenger); 0 (Receptors, Calcitonin); 0 (Receptors, Dopamine D1); 0 (Receptors, Dopamine D2); 0 (Receptors, Islet Amyloid Polypeptide); VTD58H1Z2X (Dopamine) [Em] Mês de entrada: 1512 [Cu] Atualização por classe: 161019 [Lr] Data última revisão: 161019 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 140719 [St] Status: MEDLINE [do] DOI: 10.1038/npp.2014.180

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[PMID]: 24614496 [Au] Autor: Zhu H; Wang X; Wallack M; Li H; Carreras I; Dedeoglu A; Hur JY; Zheng H; Li H; Fine R; Mwamburi M; Sun X; Kowall N; Stern RA; Qiu WQ [Ad] Endereço: Department of Pharmacology and Experimental Therapeutics, Boston University Medical Campus, Boston, MA, USA. [Ti] Título: Intraperitoneal injection of the pancreatic peptide amylin potently reduces behavioral impairment and brain amyloid pathology in murine models of Alzheimer's disease. [So] Source: Mol Psychiatry;20(2):252-62, 2015 Feb. [Is] ISSN: 1476-5578 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Amylin, a pancreatic peptide, and amyloid-beta peptides (Aß), a major component of Alzheimer's disease (AD) brain, share similar ß-sheet secondary structures, but it is not known whether pancreatic amylin affects amyloid pathogenesis in the AD brain. Using AD mouse models, we investigated the effects of amylin and its clinical analog, pramlintide, on AD pathogenesis. Surprisingly, chronic intraperitoneal (i.p.) injection of AD animals with either amylin or pramlintide reduces the amyloid burden as well as lowers the concentrations of Aß in the brain. These treatments significantly improve their learning and memory assessed by two behavioral tests, Y maze and Morris water maze. Both amylin and pramlintide treatments increase the concentrations of Aß1-42 in cerebral spinal fluid (CSF). A single i.p. injection of either peptide also induces a surge of Aß in the serum, the magnitude of which is proportionate to the amount of Aß in brain tissue. One intracerebroventricular injection of amylin induces a more significant surge in serum Aß than one i.p. injection of the peptide. In 330 human plasma samples, a positive association between amylin and Aß1-42 as well as Aß1-40 is found only in patients with AD or amnestic mild cognitive impairment. As amylin readily crosses the blood-brain barrier, our study demonstrates that peripheral amylin's action on the central nervous system results in translocation of Aß from the brain into the CSF and blood that could be an explanation for a positive relationship between amylin and Aß in blood. As naturally occurring amylin may play a role in regulating Aß in brain, amylin class peptides may provide a new avenue for both treatment and diagnosis of AD. [Mh] Termos MeSH primário: Doença de Alzheimer/complicações Agonistas dos Receptores da Amilina/uso terapêutico Polipeptídeo Amiloide das Ilhotas Pancreáticas/uso terapêutico Transtornos Mentais/tratamento farmacológico Transtornos Mentais/etiologia [Mh] Termos MeSH secundário: Doença de Alzheimer/genética Doença de Alzheimer/patologia Secretases da Proteína Precursora do Amiloide/metabolismo Peptídeos beta-Amiloides/metabolismo Precursor de Proteína beta-Amiloide/genética Animais Ácido Aspártico Endopeptidases/metabolismo Modelos Animais de Doenças Feminino Regulação da Expressão Gênica/efeitos dos fármacos Regulação da Expressão Gênica/genética Seres Humanos Masculino Aprendizagem em Labirinto/efeitos dos fármacos Camundongos Camundongos Endogâmicos C57BL Camundongos Transgênicos Mutação/genética Fragmentos de Peptídeos/metabolismo Presenilina-1/genética Escalas de Graduação Psiquiátrica [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Amylin Receptor Agonists); 0 (Amyloid beta-Peptides); 0 (Amyloid beta-Protein Precursor); 0 (Islet Amyloid Polypeptide); 0 (PSEN1 protein, human); 0 (Peptide Fragments); 0 (Presenilin-1); 0 (amyloid beta-protein (1-40)); 0 (amyloid beta-protein (1-42)); EC 3.4.- (Amyloid Precursor Protein Secretases); EC 3.4.23.- (Aspartic Acid Endopeptidases); EC 3.4.23.46 (Bace1 protein, mouse) [Em] Mês de entrada: 1603 [Cu] Atualização por classe: 161019 [Lr] Data última revisão: 161019 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 140312 [St] Status: MEDLINE [do] DOI: 10.1038/mp.2014.17

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[PMID]: 25030939 [Au] Autor: Kowalczyk R; Brimble MA; Tomabechi Y; Fairbanks AJ; Fletcher M; Hay DL [Ad] Endereço: The School of Chemical Sciences, University of Auckland, 23 Symonds St, Auckland 1010, New Zealand. m.brimble@auckland.ac.nz. [Ti] Título: Convergent chemoenzymatic synthesis of a library of glycosylated analogues of pramlintide: structure-activity relationships for amylin receptor agonism. [So] Source: Org Biomol Chem;12(41):8142-51, 2014 Nov 07. [Is] ISSN: 1477-0539 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Pramlintide (Symlin®), a synthetic analogue of the naturally occurring pancreatic hormone amylin, is currently used with insulin in adjunctive therapy for type 1 and type 2 diabetes mellitus. Herein we report a systematic study into the effect that N-glycosylation of pramlintide has on activation of amylin receptors. A highly efficient convergent synthetic route, involving a combination of solid phase peptide synthesis and enzymatic glycosylation, delivered a library of N-glycosylated variants of pramlintide bearing either GlcNAc, the core N-glycan pentasaccharide [Man3(GlcNAc)2] or a complex biantennary glycan [(NeuAcGalGlcNAcMan)2Man(GlcNAc)2] at each of its six asparagine residues. The majority of glycosylated versions of pramlintide were potent receptor agonists, suggesting that N-glycosylation may be used as a tool to optimise the pharmacokinetic properties of pramlintide and so deliver improved therapeutic agents for the treatment of diabetes and obesity. [Mh] Termos MeSH primário: Agonistas dos Receptores da Amilina/química Agonistas dos Receptores da Amilina/farmacologia Polipeptídeo Amiloide das Ilhotas Pancreáticas/síntese química Polipeptídeo Amiloide das Ilhotas Pancreáticas/farmacologia Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas/metabolismo [Mh] Termos MeSH secundário: Agonistas dos Receptores da Amilina/síntese química Relação Dose-Resposta a Droga Glicosilação Seres Humanos Polipeptídeo Amiloide das Ilhotas Pancreáticas/química Estrutura Molecular Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Amylin Receptor Agonists); 0 (Islet Amyloid Polypeptide); 0 (Receptors, Islet Amyloid Polypeptide); D3FM8FA78T (pramlintide) [Em] Mês de entrada: 1506 [Cu] Atualização por classe: 141002 [Lr] Data última revisão: 141002 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 140718 [St] Status: MEDLINE [do] DOI: 10.1039/c4ob01208a

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[PMID]: 24169554 [Au] Autor: Gingell JJ; Burns ER; Hay DL [Ad] Endereço: School of Biological Sciences (J.J.G., E.R.B., D.L.H.), The University of Auckland and Maurice Wilkins Centre (J.J.G., D.L.H.), University of Auckland, Auckland 1142, New Zealand. [Ti] Título: Activity of pramlintide, rat and human amylin but not Aß1-42 at human amylin receptors. [So] Source: Endocrinology;155(1):21-6, 2014 Jan. [Is] ISSN: 1945-7170 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Amylin is a neuroendocrine hormone involved in glucose regulation. An amylin analog, pramlintide, is used to treat insulin-requiring diabetes. Its anorexigenic actions give it potential as an obesity treatment. There are 3 amylin receptors (AMY1, AMY2, AMY3), comprising the calcitonin receptor and receptor activity-modifying proteins 1, 2, and 3, respectively. The pharmacology of pramlintide at each subtype has not been determined whereas the unrelated peptide ß-amyloid 1-42 (Aß1-42) has recently been proposed to be a specific agonist of the AMY3 receptor. We investigated the actions of Aß1-42 and pramlintide, compared with human and rat amylin at the calcitonin receptor, AMY1, AMY2, and AMY3 receptors, measuring the cAMP response in human embryonic kidney 293S and Cos 7 cells. Pramlintide activated all receptors with a slight preference for AMY1. No cAMP response was detected with Aß1-42 at any receptor, suggesting that it may not be a genuine agonist of AMY receptors. [Mh] Termos MeSH primário: Peptídeos beta-Amiloides/metabolismo Hipoglicemiantes/química Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo Fragmentos de Peptídeos/metabolismo Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas/metabolismo [Mh] Termos MeSH secundário: Sequência de Aminoácidos Agonistas dos Receptores da Amilina Animais Células COS Calcitonina/metabolismo Cercopithecus aethiops Células HEK293 Seres Humanos Polipeptídeo Amiloide das Ilhotas Pancreáticas/química Dados de Sequência Molecular Fenótipo Ratos Receptores da Calcitonina/agonistas Receptores da Calcitonina/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Amylin Receptor Agonists); 0 (Amyloid beta-Peptides); 0 (Hypoglycemic Agents); 0 (Islet Amyloid Polypeptide); 0 (Peptide Fragments); 0 (Receptors, Calcitonin); 0 (Receptors, Islet Amyloid Polypeptide); 0 (amyloid beta-protein (1-42)); 9007-12-9 (Calcitonin); D3FM8FA78T (pramlintide) [Em] Mês de entrada: 1402 [Cu] Atualização por classe: 141120 [Lr] Data última revisão: 141120 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 131031 [St] Status: MEDLINE [do] DOI: 10.1210/en.2013-1658

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MEDLINE

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[PMID]: 23956012 [Au] Autor: Yan LM; Velkova A; Tatarek-Nossol M; Rammes G; Sibaev A; Andreetto E; Kracklauer M; Bakou M; Malideli E; Göke B; Schirra J; Storr M; Kapurniotu A [Ad] Endereço: Division of Peptide Biochemistry, Technische Universität München, Emil-Erlenmeyer-Forum 5, 85354 Freising (Germany) http://pbch.wzw.tum.de/ [Ti] Título: Selectively N-methylated soluble IAPP mimics as potent IAPP receptor agonists and nanomolar inhibitors of cytotoxic self-assembly of both IAPP and Aß40. [So] Source: Angew Chem Int Ed Engl;52(39):10378-83, 2013 Sep 23. [Is] ISSN: 1521-3773 [Cp] País de publicação: Germany [La] Idioma: eng [Mh] Termos MeSH primário: Agonistas dos Receptores da Amilina Amiloide/antagonistas & inibidores Polipeptídeo Amiloide das Ilhotas Pancreáticas/química Peptidomiméticos/química Peptidomiméticos/farmacologia [Mh] Termos MeSH secundário: Sequência de Aminoácidos Amiloide/metabolismo Amiloide/ultraestrutura Peptídeos beta-Amiloides/antagonistas & inibidores Peptídeos beta-Amiloides/metabolismo Peptídeos beta-Amiloides/ultraestrutura Seres Humanos Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo Polipeptídeo Amiloide das Ilhotas Pancreáticas/ultraestrutura Metilação Dados de Sequência Molecular Fragmentos de Peptídeos/antagonistas & inibidores Fragmentos de Peptídeos/metabolismo Fragmentos de Peptídeos/ultraestrutura Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Amylin Receptor Agonists); 0 (Amyloid); 0 (Amyloid beta-Peptides); 0 (Islet Amyloid Polypeptide); 0 (Peptide Fragments); 0 (Peptidomimetics); 0 (Receptors, Islet Amyloid Polypeptide); 0 (amyloid beta-protein (40-42)) [Em] Mês de entrada: 1409 [Cu] Atualização por classe: 141120 [Lr] Data última revisão: 141120 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 130820 [St] Status: MEDLINE [do] DOI: 10.1002/anie.201302840

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