RESUMEN
We report the discovery of piperazine urea based compound 1, a potent, selective, orally bioavailable melanocortin subtype-4 receptor partial agonist. Compound 1 shows anti-obesity efficacy without potentiating erectile activity in the rodent models.
Asunto(s)
Piperazinas/química , Receptor de Melanocortina Tipo 4/agonistas , Urea/análogos & derivados , Administración Oral , Animales , Disponibilidad Biológica , Modelos Animales de Enfermedad , Perros , Evaluación Preclínica de Medicamentos , Ingestión de Alimentos/efectos de los fármacos , Haplorrinos , Ratones , Obesidad/tratamiento farmacológico , Piperazinas/farmacocinética , Piperazinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Receptor de Melanocortina Tipo 4/genética , Receptor de Melanocortina Tipo 4/metabolismo , Relación Estructura-Actividad , Urea/química , Urea/farmacocinética , Urea/uso terapéuticoRESUMEN
Design, syntheses and structure-activity relationships of N-acetylated piperazine privileged structures containing MC4R agonist compounds were described. The most potent derivatives were low nM MC4R selective full agonists. Several compounds from the series had modest pharmacokinetic properties.
Asunto(s)
Ligandos , Receptor de Melanocortina Tipo 4/agonistas , Animales , Humanos , Piperazina , Piperazinas/síntesis química , Piperazinas/química , Piperazinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Receptor de Melanocortina Tipo 4/metabolismo , Relación Estructura-ActividadRESUMEN
We report the design, synthesis and properties of spiroindane based compound 1, a potent, selective, orally bioavailable, non-peptide melanocortin subtype-4 receptor agonist. Compound 1 shows excellent erectogenic activity in the rodent models.
Asunto(s)
Disfunción Eréctil/tratamiento farmacológico , Indanos/química , Indanos/uso terapéutico , Receptor de Melanocortina Tipo 4/agonistas , Receptor de Melanocortina Tipo 4/metabolismo , Compuestos de Espiro/química , Compuestos de Espiro/uso terapéutico , Animales , Células CHO , Cricetinae , Cricetulus , Perros , Haplorrinos , Humanos , Indanos/farmacocinética , Indanos/farmacología , Masculino , Ratones , Estructura Molecular , Unión Proteica , Ratas , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
A series of 3-amino-1,5-benzodiazepinones were synthesized and evaluated as potential sodium channel blockers in a functional, membrane potential-based assay. One member of this series displayed subnanomolar, state-dependent sodium channel block, and was orally efficacious in a mouse model of epilepsy.
Asunto(s)
Anticonvulsivantes/farmacología , Benzodiazepinonas/farmacología , Epilepsia/tratamiento farmacológico , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Bloqueadores de los Canales de Sodio/farmacología , Animales , Anticonvulsivantes/síntesis química , Anticonvulsivantes/farmacocinética , Benzodiazepinonas/síntesis química , Benzodiazepinonas/farmacocinética , Electrofisiología , Electrochoque , Epilepsia/metabolismo , Canales de Potasio Éter-A-Go-Go/metabolismo , Transferencia Resonante de Energía de Fluorescencia , Humanos , Ratones , Estructura Molecular , Ratas , Bloqueadores de los Canales de Sodio/síntesis química , Bloqueadores de los Canales de Sodio/farmacocinéticaRESUMEN
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.
Asunto(s)
Hipoglucemiantes/farmacología , Receptores de Somatostatina/agonistas , Animales , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Perros , Glucagón/metabolismo , Hormona del Crecimiento/metabolismo , Técnicas In Vitro , Insulina/metabolismo , Insulina/farmacología , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Obesos , Ratas , Receptores de Somatostatina/genéticaRESUMEN
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.
Asunto(s)
Compuestos Aza/farmacología , Ingestión de Alimentos/efectos de los fármacos , Erección Peniana/efectos de los fármacos , Piperazinas/farmacología , Piperidinas/farmacología , Receptor de Melanocortina Tipo 4/agonistas , Animales , Compuestos Aza/síntesis química , Humanos , Masculino , Microsomas Hepáticos/metabolismo , Piperazinas/química , Piperidinas/síntesis química , Unión Proteica , Quinuclidinas/química , Ratas , Ratas Sprague-Dawley , Roedores , Relación Estructura-Actividad , Factores de TiempoRESUMEN
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.
Asunto(s)
Erección Peniana/efectos de los fármacos , Receptores de Corticotropina/agonistas , Tetrahidroisoquinolinas , Proteína Relacionada con Agouti , Animales , Unión Competitiva , Canfanos/farmacología , Relación Dosis-Respuesta a Droga , Isoquinolinas/farmacología , Masculino , Erección Peniana/fisiología , Fragmentos de Péptidos/farmacología , Péptidos Cíclicos/farmacología , Piperazinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptor de Melanocortina Tipo 4 , Receptores de Corticotropina/antagonistas & inhibidores , Triazoles/farmacologíaRESUMEN
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.
Asunto(s)
Isoquinolinas/síntesis química , Receptores de Corticotropina/agonistas , Tetrahidroisoquinolinas , Triazoles/síntesis química , Animales , Unión Competitiva , Disponibilidad Biológica , Células CHO , Cricetinae , Perros , Ingestión de Alimentos/efectos de los fármacos , Humanos , Isoquinolinas/química , Isoquinolinas/farmacología , Conformación Molecular , Erección Peniana/efectos de los fármacos , Ratas , Receptor de Melanocortina Tipo 3 , Receptor de Melanocortina Tipo 4 , Receptores de Melanocortina , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacologíaRESUMEN
By using a combination of genetic, pharmacological, and anatomical approaches, we show that the melanocortin 4 receptor (MC4R), implicated in the control of food intake and energy expenditure, also modulates erectile function and sexual behavior. Evidence supporting this notion is based on several findings: (i) a highly selective non-peptide MC4R agonist augments erectile activity initiated by electrical stimulation of the cavernous nerve in wild-type but not Mc4r-null mice; (ii) copulatory behavior is enhanced by administration of a selective MC4R agonist and is diminished in mice lacking Mc4r; (iii) reverse transcription (RT)-PCR and non-PCR based methods demonstrate MC4R expression in rat and human penis, and rat spinal cord, hypothalamus, brainstem, pelvic ganglion (major autonomic relay center to the penis), but not in rat primary corpus smooth muscle cavernosum cells; and (iv) in situ hybridization of glans tissue from the human and rat penis reveal MC4R expression in nerve fibers and mechanoreceptors in the glans of the penis. Collectively, these data implicate the MC4R in the modulation of penile erectile function and provide evidence that MC4R-mediated proerectile responses may be activated through neuronal circuitry in spinal cord erectile centers and somatosensory afferent nerve terminals of the penis. Our results provide a basis for the existence of MC4R-controlled neuronal pathways that control sexual function.
Asunto(s)
Copulación/fisiología , Pene/fisiología , Receptores de Corticotropina/fisiología , Conducta Sexual Animal/fisiología , Animales , Presión Sanguínea/fisiología , Cartilla de ADN , ADN Complementario , Estimulación Eléctrica , Metabolismo Energético/fisiología , Conducta Alimentaria/fisiología , Hibridación in Situ , Técnicas In Vitro , Presión Intracraneal/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Fibras Nerviosas/fisiología , Pene/inervación , Receptor de Melanocortina Tipo 4 , Receptores de Corticotropina/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ribonucleasa PancreáticaRESUMEN
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.