ABSTRACT
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.
Subject(s)
Piperazines/chemistry , Piperazines/pharmacology , Receptor, Melanocortin, Type 4/drug effects , Ligands , Molecular Structure , Piperazines/chemical synthesis , Receptor, Melanocortin, Type 4/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Glycine/chemistry , Glycine/pharmacology , Receptors, Metabotropic Glutamate/agonists , Receptors, Metabotropic Glutamate/metabolism , Crystallography, X-Ray , Cyclization , Glycine/chemical synthesis , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Benzene Derivatives/chemistry , Benzene Derivatives/metabolism , Piperazines/chemistry , Piperazines/metabolism , Receptors, Melanocortin/metabolism , Ligands , Molecular Structure , Piperazine , Receptors, Melanocortin/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
(+)-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.
Subject(s)
Alanine/analogs & derivatives , Anti-Anxiety Agents/chemical synthesis , Bridged Bicyclo Compounds/chemical synthesis , Dipeptides/chemical synthesis , Prodrugs/chemical synthesis , Receptors, Metabotropic Glutamate/agonists , Administration, Oral , Alanine/administration & dosage , Alanine/chemical synthesis , Alanine/pharmacokinetics , Animals , Anti-Anxiety Agents/pharmacokinetics , Anti-Anxiety Agents/pharmacology , Biological Availability , Bridged Bicyclo Compounds/administration & dosage , Bridged Bicyclo Compounds/pharmacokinetics , Bridged Bicyclo Compounds/pharmacology , Cell Line, Tumor , Cricetinae , Cricetulus , Dipeptides/pharmacokinetics , Dipeptides/pharmacology , Humans , Male , Peptide Transporter 1 , Prodrugs/pharmacokinetics , Prodrugs/pharmacology , Rats , Rats, Sprague-Dawley , Reflex, Startle/drug effects , Stereoisomerism , Structure-Activity Relationship , Symporters/metabolismABSTRACT
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.
Subject(s)
Brain/drug effects , Cyclopropanes/chemistry , Glycine/analogs & derivatives , Glycine/chemistry , Isotope Labeling/methods , Receptors, Metabotropic Glutamate/metabolism , Tritium , Aminobutyrates/pharmacology , Animals , Brain/metabolism , Cell Line , Cell Membrane/metabolism , Cyclopropanes/pharmacology , Glutamic Acid/pharmacology , Glycine/pharmacology , Humans , Ligands , RatsABSTRACT
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.
Subject(s)
Glycine/chemical synthesis , Receptors, Metabotropic Glutamate/agonists , Administration, Oral , Animals , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Cyclic AMP/biosynthesis , Fear , Glycine/analogs & derivatives , Glycine/chemistry , Glycine/pharmacology , In Vitro Techniques , Male , Motor Activity/drug effects , Rats , Rats, Sprague-Dawley , Reflex, Startle/drug effects , Stereoisomerism , Structure-Activity RelationshipABSTRACT
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.