RESUMEN
Aliphatic carbocyclic replacement of the benzyl group of compound 1 yielded compounds with high affinity for the melanocortin-4 receptor (MC4R). Compounds with a cyclohexyl group showed a consistent high affinity, while different polar groups with less basicity were good replacements for the original diethyl amines. Substitution of the polar group found in these privileged structures with an aliphatic moiety produced compounds with high affinity for MC4R.
Asunto(s)
Piperazinas/química , Piperazinas/farmacología , Receptor de Melanocortina Tipo 4/efectos de los fármacos , Ligandos , Estructura Molecular , Piperazinas/síntesis química , Receptor de Melanocortina Tipo 4/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The synthesis of a series of C3'-cis-substituted carboxycyclopropyl glycines bearing a wide variety of functional groups is described, and the structure-activity relationship for this series as agonists of group II metabotropic glutamate receptors is reported.
Asunto(s)
Glicina/química , Glicina/farmacología , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/metabolismo , Cristalografía por Rayos X , Ciclización , Glicina/síntesis química , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Replacement of the aryl piperazine moiety in compound 1 with a variety of substituted benzylic piperazines (6) yields compounds that afford melanocortin receptor 4 (MCR4) activity. Analogs with ortho substitution on the aromatic ring afforded the highest affinity. Resolution of the stereocenter of the benzylic piperazine based privileged structure revealed that the R-enantiomer was more active.
Asunto(s)
Derivados del Benceno/química , Derivados del Benceno/metabolismo , Piperazinas/química , Piperazinas/metabolismo , Receptores de Melanocortina/metabolismo , Ligandos , Estructura Molecular , Piperazina , Receptores de Melanocortina/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
(+)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (1), also known as LY354740, is a highly potent and selective agonist for group II metabotropic glutamate receptors (mGlu receptors 2 and 3) tested in clinical trials. It has been shown to block anxiety in the fear-potentiated startle model. Its relatively low bioavailability in different animal species drove the need for an effective prodrug form that would produce a therapeutic response at lower doses for the treatment of anxiety disorders. We have investigated the increase of intestinal absorption of this compound by targeting the human peptide transporter hPepT1 for active transport of di- and tripeptides derived from 1. We have found that oral administration of an N dipeptide derivative of 1 (12a) in rats shows up to an 8-fold increase in drug absorption and a 300-fold increase in potency in the fear-potentiated startle model in rats when compared with the parent drug 1.
Asunto(s)
Alanina/análogos & derivados , Ansiolíticos/síntesis química , Compuestos Bicíclicos con Puentes/síntesis química , Dipéptidos/síntesis química , Profármacos/síntesis química , Receptores de Glutamato Metabotrópico/agonistas , Administración Oral , Alanina/administración & dosificación , Alanina/síntesis química , Alanina/farmacocinética , Animales , Ansiolíticos/farmacocinética , Ansiolíticos/farmacología , Disponibilidad Biológica , Compuestos Bicíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos con Puentes/farmacocinética , Compuestos Bicíclicos con Puentes/farmacología , Línea Celular Tumoral , Cricetinae , Cricetulus , Dipéptidos/farmacocinética , Dipéptidos/farmacología , Humanos , Masculino , Transportador de Péptidos 1 , Profármacos/farmacocinética , Profármacos/farmacología , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto/efectos de los fármacos , Estereoisomerismo , Relación Estructura-Actividad , Simportadores/metabolismoRESUMEN
We report herein the synthesis of the tritium labeled isotopomer of 1 and its use as a radioligand to label mGlu8 receptors in rat forebrain membranes as well as cloned human recombinant mGlu receptors. [(3)H]-1 was synthesized by the NaBT(4) reduction of an activated analog of 5. [(3)H]-1 bound appreciably to recombinant human mGlu2, mGlu3 and mGlu8 receptors and to rat forebrain membranes and was displaced by L-glutamate and L-(+)-2 amino-4-phosphonobutyric acid. The results indicate that [(3)H]-1 should be a useful ligand for the study of mGluR2, 3, and 8 receptors in cloned cell lines and possibly brain tissue.
Asunto(s)
Encéfalo/efectos de los fármacos , Ciclopropanos/química , Glicina/análogos & derivados , Glicina/química , Marcaje Isotópico/métodos , Receptores de Glutamato Metabotrópico/metabolismo , Tritio , Aminobutiratos/farmacología , Animales , Encéfalo/metabolismo , Línea Celular , Membrana Celular/metabolismo , Ciclopropanos/farmacología , Ácido Glutámico/farmacología , Glicina/farmacología , Humanos , Ligandos , RatasRESUMEN
The asymmetric synthesis and biological activity of (2S,1'S,2'R,3'R)-2-(2'-carboxy-3'-hydroxymethylcyclopropyl) glycine ((+)-3) is described. This novel C-3' substituted carboxy cyclopropyl glycine is a highly potent group 2 and group 3 mGluR agonist that has proven to be orally active in both fear potentiated startle (animal model for anxiety) and PCP-induced motor activation (animal model for psychosis) assays in rats.
Asunto(s)
Glicina/síntesis química , Receptores de Glutamato Metabotrópico/agonistas , Administración Oral , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , AMP Cíclico/biosíntesis , Miedo , Glicina/análogos & derivados , Glicina/química , Glicina/farmacología , Técnicas In Vitro , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto/efectos de los fármacos , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The asymmetric synthesis and biological activity of (2S,1'S,2'S,3'R)-2-(2'-carboxy-3'-methylcyclopropyl) glycine 7 and its epimer at the C3' center 6 are described. Compound 7 is a highly potent and selective agonist for group 2 metabotropric glutamate receptors (mGluRs). It is also systemically 4 orders of magnitude more active in the fear-potentiated startle model of anxiety in rats than the rigid constrained bicyclic system LY354740. Therefore, we have shown that high molecular complexity of conformationally constrained bicyclic systems is not a requirement to achieve highly selective and potent group 2 mGluRs agonists.