Preclinical evaluation of the abuse potential of the analgesic bicifadine.

The abuse liability of the analgesic bicifadine was investigated in animal models used to predict the abuse potential of psychostimulants in humans. Bicifadine, cocaine, d-amphetamine, bupropion, and desipramine were evaluated for the production of cocaine-like discriminative stimulus effects in rats. Cocaine, d-amphetamine, and bupropion dose-dependently and fully substituted for cocaine.

The triple uptake inhibitor (1R,5S)-(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0] hexane hydrochloride (DOV 21947) reduces body weight and plasma triglycerides in rodent models of diet-induced obesity.

Selective inhibitors of biogenic amine (e.g., serotonin, norepinephrine, and dopamine) uptake exhibit varying degrees of safety and efficacy as antiobesity agents.

In vivo pharmacological characterization of the structurally novel, potent, selective mGlu2/3 receptor agonist LY404039 in animal models of psychiatric disorders.

Rationale: Data from both preclinical and clinical studies have provided proof of concept that modulation of limbic and forebrain glutamate, via mGlu2/3 receptor agonists, might provide therapeutic benefits in many psychiatric disorders including schizophrenia and anxiety.

Objective: The aim of this study was to assess the efficacy of a structurally novel, potent, selective mGlu2/3 receptor agonist with improved bioavailability (LY404039) in animal models predictive of antipsychotic and anxiolytic efficacy.

Materials And Methods: LY404039 was assessed in amphetamine- and phencyclidine-induced hyperlocomotion, conditioned avoidance responding, fear-potentiated startle, marble burying, and rotarod behavioral tests.

Preclinical and clinical pharmacology of DOV 216,303, a "triple" reuptake inhibitor.

DOV 216,303 [(+/-)-1-(3,4-dichlorophenyl)-3-azabicyclo-[3.1.0]hexane hydrochloride] is the prototype of a class of compounds referred to as "triple" reuptake inhibitors.

Dipeptides as effective prodrugs of the unnatural amino acid (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), a selective group II metabotropic glutamate receptor agonist.

(+)-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.

Metabotropic glutamate 2 receptor potentiators: receptor modulation, frequency-dependent synaptic activity, and efficacy in preclinical anxiety and psychosis model(s).

Rationale: To increase subtype selectivity and provide a novel means to alter receptor function, we discovered and characterization potentiators for the metabotropic glutamate 2 receptor (mGlu2).

Methods And Results: A class of 3-pyridylmethylsulfonamides (e.g.

(2S,1'S,2'R,3'R)-2-(2'-Carboxy-3'-hydroxymethylcyclopropyl) glycine is a highly potent group 2 and 3 metabotropic glutamate receptor agonist with oral activity.

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.

Discovery of allosteric potentiators for the metabotropic glutamate 2 receptor: synthesis and subtype selectivity of N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2- trifluoroethylsulfonyl)pyrid-3-ylmethylamine.

This report describes recently discovered novel allosteric modulators of metabotropic glutamate2 (mGlu2) receptors. These pyridylmethylsulfonamides (e.g.

Inhibition of group I metabotropic glutamate receptor responses in vivo in rats by a new generation of carboxyphenylglycine-like amino acid antagonists.

A series of novel group I metabotropic glutamate receptor (mGlu) antagonists have been designed on the basis of the 4-carboxyphenylglycine pharmacophore. The compounds are either mGlu1 receptor selective or equipotent for both mGlu1 and mGlu5 receptors and have IC(50) values ranging from 1 to 30 microM determined by phosphoinositide hydrolysis (PI) assay in vitro. All the compounds produced dose-dependent inhibition of group I mGlu receptor agonist (RS)-3,5-dihydroxyphenylglycine (DHPG)-induced limbic seizure responses in mice with ED(50) values ranging from 9 nmol for LY393053 to 138 nmol for LY339840 after intracerebroventricular injection and were more potent than the mGlu1 receptor antagonist 1-aminoindan-1,5-dicarboxylic acid (ED(50)=477 nmol).

The anxiolytic action of mGlu2/3 receptor agonist, LY354740, in the fear-potentiated startle model in rats is mechanistically distinct from diazepam.

The fear-potentiated startle paradigm has been characterized for drugs that act via ionotropic (NMDA and AMPA/kainate receptor) glutamate receptor mechanisms. Previous studies have shown that the potent systemically active mGlu2/3 receptor agonist, LY354740, effectively reduced the expression of fear-potentiated startle responses in rats. The present study examined the effects of LY354740 in a pre- versus post-fear conditioning paradigm and compared the effects to diazepam.