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1.
Bioorg Med Chem Lett ; 21(8): 2330-4, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21439820
2.
Bioorg Med Chem Lett ; 20(7): 2106-10, 2010 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-20207541
3.
Bioorg Med Chem Lett ; 18(6): 1963-6, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18289851
4.
Endocrinology ; 147(10): 4664-73, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16857751

RESUMO

Somatostatin inhibits both glucagon and insulin secretion. Glucagon significantly contributes to hyperglycemia in type 2 diabetes. Despite its function in the inhibition of glucagon secretion, somatostatin fails to reduce hyperglycemia in type 2 diabetes, due to a parallel suppression of insulin secretion. Five pharmacologically distinct somatostatin receptor subtypes (sst(1)-sst(5)) mediate the effects of somatostatin on a cellular level. Pancreatic A cells express sst(2), whereas B cells express sst(5). In this study, we describe a novel approach to the treatment of type 2 diabetes using a highly sst(2)-selective, nonpeptide agonist (compound 1). Compound 1 effectively inhibited glucagon secretion from pancreatic islets isolated from wild-type mice, whereas glucagon secretion from sst(2)-deficient islets was not suppressed. Compound 1 did not influence nonfasted insulin concentration. In sst(2)-deficient mice, compound 1 did not have any effects on glucagon or glucose levels, confirming its sst(2) selectivity. In animal models of type 2 diabetes in the nonfasted state, circulating glucagon and glucose levels were decreased after treatment with compound 1. In the fasting state, compound 1 lowered blood glucose by approximately 25%. In summary, small-molecule sst(2)-selective agonists that suppress glucagon secretion offer a novel approach toward the development of orally bioavailable drugs for treatment of type 2 diabetes.


Assuntos
Hipoglicemiantes/farmacologia , Receptores de Somatostatina/agonistas , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Cães , Glucagon/metabolismo , Hormônio do Crescimento/metabolismo , Técnicas In Vitro , Insulina/metabolismo , Insulina/farmacologia , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Ratos , Receptores de Somatostatina/genética
5.
Bioorg Med Chem Lett ; 15(15): 3501-5, 2005 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-15982875

RESUMO

A novel isoquinuclidine containing selective melanocortin subtype-4 receptor small molecule agonist, 3 (RY764), is reported. Its in vivo characterization revealed mechanism-based food intake reduction and erectile activity augmentation in rodents.


Assuntos
Compostos Aza/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Ereção Peniana/efeitos dos fármacos , Piperazinas/farmacologia , Piperidinas/farmacologia , Receptor Tipo 4 de Melanocortina/agonistas , Animais , Compostos Aza/síntese química , Humanos , Masculino , Microssomos Hepáticos/metabolismo , Piperazinas/química , Piperidinas/síntese química , Ligação Proteica , Quinuclidinas/química , Ratos , Ratos Sprague-Dawley , Roedores , Relação Estrutura-Atividade , Fatores de Tempo
6.
Eur J Pharmacol ; 454(1): 71-9, 2002 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-12409007

RESUMO

Melanocortin peptide agonists, alpha-melanocyte stimulating hormone (alpha-MSH) and melanotan-II, stimulate erectile activity in a variety of species, including man. Since neither peptide discriminates amongst melanocortin receptors, it is not clear which subtype mediates these pro-erectile effects. Here, we present data that melanocortin-induced erectogenesis is mediated by melanocortin MC(4) receptors. Systemic administration of a melanocortin MC(4) receptor agonist (N-[(3R)-1,2,3,4-tetrahydroisoquinolinium-3-ylcarbonyl]-(1R)-1-(4-chlorobenzyl)-2-[4-cyclohexyl-4-(1H-1,2,4-triazol-1ylmethyl)piperidin-1-yl]-2-oxoethylamine; THIQ) with high selectivity over other melanocortin receptors enhanced intracavernosal pressure and stimulated erectile activity in rats ex copula. THIQ dose-dependently (1-5 mg/kg, i.v.) increased the total number of erections, to an extent comparable or greater than that produced by apomorphine (0.025 mg/kg, s.c.). Central administration of THIQ (20 microg, intracerebroventricular (i.c.v.)) increased the number of reflexive penile erections; whereas administration of both a nonselective endogenous melanocortin MC(4) receptor antagonist (agouti-related protein (AgRP), 5.5. microg, i.c.v.) and a melanocortin MC(4) receptor preferring antagonist (MPB10, 1 mg/kg, i.v.) blocked THIQ-induced erectogenesis. These pro-erectile effects were also attenuated by systemic or central administration of an oxytocin antagonist (L-368899, 1 mg/kg, i.v.). Thus, melanocortin MC(4) receptor activation is sufficient for erectogenesis and these effects may involve oxytocinergic pathways.


Assuntos
Ereção Peniana/efeitos dos fármacos , Receptores da Corticotropina/agonistas , Tetra-Hidroisoquinolinas , Proteína Relacionada com Agouti , Animais , Ligação Competitiva , Canfanos/farmacologia , Relação Dose-Resposta a Droga , Isoquinolinas/farmacologia , Masculino , Ereção Peniana/fisiologia , Fragmentos de Peptídeos/farmacologia , Peptídeos Cíclicos/farmacologia , Piperazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor Tipo 4 de Melanocortina , Receptores da Corticotropina/antagonistas & inibidores , Triazóis/farmacologia
7.
J Med Chem ; 45(21): 4589-93, 2002 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-12361385

RESUMO

Synthetic and natural peptides that act as nonselective melanocortin receptor agonists have been found to be anorexigenic and to stimulate erectile activity. We report the design and development of 1, a potent, selective (1184-fold vs MC3R, 350-fold vs MC5R), small-molecule agonist of the MC4 receptor. Pharmacological testing confirms the food intake lowering effects of MC4R agonism and suggests another role for the receptor in the stimulation of erectile activity.


Assuntos
Isoquinolinas/síntese química , Receptores da Corticotropina/agonistas , Tetra-Hidroisoquinolinas , Triazóis/síntese química , Animais , Ligação Competitiva , Disponibilidade Biológica , Células CHO , Cricetinae , Cães , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Isoquinolinas/química , Isoquinolinas/farmacologia , Conformação Molecular , Ereção Peniana/efeitos dos fármacos , Ratos , Receptor Tipo 3 de Melanocortina , Receptor Tipo 4 de Melanocortina , Receptores de Melanocortina , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologia
8.
Br J Pharmacol ; 136(5): 693-700, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12086978

RESUMO

1. Using an in vivo model of erectile activity, the effects of sildenafil were studied in mice lacking neuronal or endothelial nitric oxide synthase (nNOS and eNOS, respectively). 2. Under pentobarbitone anaesthesia, intracavernous pressure (ICP) and mean arterial pressure (MAP) were monitored continuously in wild-type, nNOS-/- and eNOS-/- mice. The magnitude of erectile activity was quantified as the ratio of ICP to MAP. 3. No differences in basal ICP or MAP were observed amongst wild-type, eNOS-/- and nNOS-/- mice. Electrical stimulation of the cavernous nerve (ESCN; 4.0 V, 16 Hz, 1 ms, 30 s) evoked increases in ICP and ICP/MAP as well as penile tumescence. Responses to ESCN were reduced in nNOS-/-, but not in eNOS-/- mice. 4. L-NAME (50 mg kg(-1), i.v.) significantly increased MAP and attenuated erectile responses in both wild-type and eNOS-/- mice. 5. Sildenafil (1 mg kg(-1), i.v.) augmented electrically-evoked erectile activity in a voltage-dependent manner in wild-type mice and facilitated erectile responses in eNOS-/- mice. By contrast, sildenafil failed to augment the diminished erectile responses in mice lacking the nNOS isoform. 5. These data reveal the relative importance of nNOS, compared to eNOS, as the critical NOS isoform in the control of erectile function and illustrate that the nNOS isoform is required for sildenafil-induced facilitation of erectile responses in vivo in mice.


Assuntos
Disfunção Erétil/enzimologia , Óxido Nítrico Sintase/deficiência , Ereção Peniana/efeitos dos fármacos , Piperazinas/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Estimulação Elétrica/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo I , Óxido Nítrico Sintase Tipo II , Óxido Nítrico Sintase Tipo III , Ereção Peniana/fisiologia , Purinas , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Citrato de Sildenafila , Sulfonas
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