RESUMO
Four new sesterterpenoids, ansellone B (4), phorbadione (5), secoepoxyansellone A (6), and alotaketal C (7), have been isolated from specimens of the sponge Phorbas sp. collected in British Columbia. Ansellone B (4) has an unprecedented heterocyclic skeleton featuring an oxocane ring, and secoepoxyansellone A (6) is the first example of the degraded "secoansellane" sesterterpenoid carbon skeleton. Alotaketal C (7) is an activator of cAMP signaling in HEK cells.
Assuntos
Poríferos/química , Sesterterpenos/isolamento & purificação , Animais , AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Conformação Molecular , Sesterterpenos/química , Sesterterpenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Diabetes is a debilitating disease characterized by chronic hyperglycemia and is often associated with obesity. With diabetes and obesity incidence on the rise, it is imperative to develop novel therapeutics that will not only lower blood glucose levels, but also combat the associated obesity. The G protein-coupled receptors (GPCRs) for glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon are emerging as targets to treat both hyperglycemia and obesity. GIP is rapidly released from intestinal K-cells following food intake and stimulates glucose-dependent insulin secretion from ß-cells and the storage of fat in adipocytes. Both GIP receptor agonists and antagonists have been demonstrated to display therapeutic potential to treat diabetes and obesity. Similar to GIP, GLP-1 is released from intestinal L-cells following food intake and potentiates glucose-dependent insulin secretion from ß-cells. In addition, GLP-1 reduces glucagon levels, suppresses gastric emptying and reduces food intake. As such, GLP-1 receptor agonists effectively lower blood glucose levels and reduce weight. Finally, glucagon is released from α-cells and raises blood glucose levels during the fasting state by stimulating gluconeogenesis and glycogenolysis in the liver. Thus, molecules that antagonize the glucagon receptor may be used to treat hyperglycemia. Given the structural similarity of these peptides and their receptors, molecules capable of agonizing or antagonizing combinations of these receptors have recently been suggested as even better therapeutics. Here we review the biology of GIP, GLP-1 and glucagon and examine the various therapeutic strategies to activate and antagonize the receptors of these peptides.
Assuntos
Diabetes Mellitus/tratamento farmacológico , Terapia de Alvo Molecular , Obesidade/tratamento farmacológico , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores dos Hormônios Gastrointestinais/antagonistas & inibidores , Receptores de Glucagon/antagonistas & inibidores , Animais , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/uso terapêutico , Diabetes Mellitus/fisiopatologia , Receptor do Peptídeo Semelhante ao Glucagon 1 , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Terapia de Alvo Molecular/métodos , Obesidade/fisiopatologia , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Receptores dos Hormônios Gastrointestinais/fisiologia , Receptores de Glucagon/agonistas , Receptores de Glucagon/fisiologiaRESUMO
Ansellone A (1) has been isolated from the dorid nudibranch Cadlina luteomarginata and the sponge Phorbas sp. It has the new "ansellane" sesterterpenoid carbon skeleton, and it activates the cAMP signaling pathway.
Assuntos
AMP Cíclico/metabolismo , Gastrópodes/química , Poríferos/química , Sesterterpenos/isolamento & purificação , Sesterterpenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem CelularRESUMO
The new sesterterpenoids alotaketals A (1) and B (2) have been isolated from extracts of the marine sponge Hamigera sp. collected in Papua New Guinea. Their chemical structures were elucidated by analysis of spectroscopic data. Alotaketals A and B have the unprecedented alotane carbon skeleton, and they activate the cAMP cell signaling pathway with EC(50)'s of 18 and 240 nM, respectively.