ABSTRACT
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. Bicifadine and desipramine produced a maximum mean cocaine-lever selection of 80 and 69%, respectively, but doses yielding peak substitution strongly suppressed response rates. Microdialysis studies in normal waking rats indicated that d-amphetamine increased dopamine levels in the nucleus accumbens and striatum to a much greater degree than bicifadine, but bicifadine increased 5-hydroxytryptamine levels in the nucleus accumbens and striatum more than d-amphetamine. Bicifadine was also tested for intravenous self-administration in rhesus monkeys experienced with cocaine administration. Reinforcing effects of bicifadine were observed in only two of four subjects, whereas cocaine, d-amphetamine, and bupropion served as reinforcers in all four monkeys. When evaluated under a progressive ratio procedure, no dose of bicifadine maintained responding to the extent of cocaine, d-amphetamine, or bupropion. The discriminative stimulus effects associated with bicifadine were similar, but not identical, to those of psychostimulants. Although bicifadine maintained self-administration behavior in some subjects, its reinforcing efficacy was very low relative to cocaine, d-amphetamine, and bupropion. These results are consistent with the microdialysis findings of lower dopamine levels and higher 5-hydroxytryptamine levels after administration of bicifadine relative to d-amphetamine. Overall, the current findings support a low abuse potential of bicifadine, more resembling that of antidepressants than psychostimulants.
Subject(s)
Analgesics/administration & dosage , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Substance-Related Disorders/metabolism , Animals , Brain/drug effects , Brain/metabolism , Discrimination Learning/drug effects , Discrimination Learning/physiology , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Macaca mulatta , Male , Rats , Rats, Sprague-Dawley , Self Administration , Substance-Related Disorders/etiologyABSTRACT
Selective inhibitors of biogenic amine (e.g., serotonin, norepinephrine, and dopamine) uptake exhibit varying degrees of safety and efficacy as antiobesity agents. Moreover, preclinical findings suggest that the combined inhibition of monoamine neurotransmitter transporters synergistically enhances antiobesity activity. (1R,5S)-(+)-1-(3,4-Dichlorophenyl)-3-azabicyclo-[3.1.0] hexane hydrochloride (DOV 21947) inhibits norepinephrine, 5-hydroxytryptamine, and dopamine uptake, and it reduces body weight in rodent models of diet-induced obesity (DIO). DIO rats treated orally with DOV 21947 for 1 to 24 days showed significantly lower body weights than vehicle-treated DIO rats. The decrease in body weight resulted specifically from a loss of retroperitoneal and mesenteric depots of white adipose tissue. DOV 21947 also reduced daily food intake in DIO rats, but consumption returned to control levels after 11 days of treatment. With the exception of a decrease in triglyceride levels, blood chemistry was unaltered after 24 days of DOV 21947 treatments. DOV 21947 had no effect on motor activity. Although DOV 21947 increased respiratory rate and decreased the tidal volume of normal rats, it did not alter the minute volume. In addition, DOV 21947 did not significantly affect blood pressure, heart rate, electrocardiographic indices or body temperature in telemeterized dogs. However, it caused a sustained, but reversible reduction in the rate of body weight gain for as long as 6 months in normal rats, and for up to 1 year in normal dogs. In summary, DOV 21947 is effective in causing a sustained and selective reduction in fat content and triglyceride levels in animal models of obesity without significantly altering vital organ function.
Subject(s)
Aza Compounds/therapeutic use , Body Weight/drug effects , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Dietary Fats/blood , Disease Models, Animal , Obesity/drug therapy , Triglycerides/blood , Animals , Anti-Obesity Agents/pharmacology , Anti-Obesity Agents/therapeutic use , Aza Compounds/pharmacology , Body Weight/physiology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cardiovascular System/drug effects , Dietary Fats/adverse effects , Dogs , Dose-Response Relationship, Drug , Female , Male , Mice , Mice, Inbred C57BL , Neurotransmitter Uptake Inhibitors/pharmacology , Neurotransmitter Uptake Inhibitors/therapeutic use , Obesity/blood , Rats , Rats, Sprague-Dawley , Weight Gain/drug effects , Weight Gain/physiologyABSTRACT
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. Monoamine release and turnover were assessed using microdialysis and ex vivo tissue levels. RESULTS: LY404039 attenuated amphetamine- and phencyclidine-induced hyperlocomotion (3-30 and 10 mg/kg, respectively). LY404039 (3-10 mg/kg) inhibited conditioned avoidance responding. LY404039 also reduced fear-potentiated startle in rats (3-30 microg/kg) and marble burying in mice (3-10 mg/kg), indicating anxiolytic-like effects. Importantly, LY404039 did not produce sedative effects or motor impairment as measured by rotarod performance and lack of escape failures in the conditioned avoidance task (at doses up to 30 and 10 mg/kg, respectively). LY404039 (10 mg/kg) also increased dopamine and serotonin release/turnover in the prefrontal cortex. CONCLUSIONS: These results demonstrate the broad preclinical efficacy of LY404039 across multiple animal models of antipsychotic and anxiolytic efficacy. Additionally, this compound modulates mesocortical neurotransmission and provides a novel mechanism for the treatment of psychiatric disorders that may be associated with improved efficacy and reduced incidence of undesirable side effects. As glutamatergic dysfunction has been linked to the etiology of schizophrenia, clinical studies with more potent mGlu2/3 agonists, such as LY404039, may be useful to explore the validity of this hypothesis.
Subject(s)
Behavior, Animal/drug effects , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cyclic S-Oxides/pharmacology , Mental Disorders/drug therapy , Receptors, Metabotropic Glutamate/agonists , Amino Acids/pharmacology , Amphetamine/pharmacology , Animals , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Cyclic S-Oxides/chemistry , Cyclic S-Oxides/therapeutic use , Diazepam/pharmacology , Disease Models, Animal , Dose-Response Relationship, Drug , Male , Mental Disorders/psychology , Mice , Molecular Structure , Motor Activity/drug effects , Phencyclidine/pharmacology , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Rats , Rats, Inbred F344 , Rats, Sprague-Dawley , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Xanthenes/pharmacologyABSTRACT
(+)-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
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., 3-MPPTS; 2,2,2-trifluoro-N-[3-(2-methoxyphenoxy)phenyl]-N-(3-pyridinylmethyl)-ethanesulfonamide) were found to be potent, subtype-selective potentiators of human and rat mGlu2. The sulfonamides increased agonist potency in functional assays but did not displace orthosteric radiolabeled antagonist or agonist binding to cloned mGlu2 receptors. Rather, the modulators increased the affinity of most of the orthosteric agonists including glutamate, DCG-IV (2S,2'R,3'R)-2-(2',3'-dicarboxylcyclopropyl)glycine), and LY354740 (1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-bicaroxylate monohydrate). In striatal brain slices, LY354740 inhibited evoked excitatory postsynaptic potentials (EPSPs) equally well following either a low- (0.06 Hz) or high (4 Hz)-frequency stimulation of corticostriatal afferents. In contrast, the mGlu2 potentiator cyPPTS (2,2,2-trifluoro-N-[3-(cyclopentyloxy)phenyl]-N-(3-pyridinylmethyl)-ethanesulfonamide) inhibited striatal EPSPs only at higher frequencies of stimulation (2 and 4 Hz). Several sulfonamides including 4-MPPTS, 4-APPES (N-[4-(4-carboxamidophenoxy)phenyl]-N-(3-pyridinylmethyl)-ethanesulfonamide hydrochloride monohydrate) and/or CBiPES N-[4'-cyano-biphenyl-3-yl)-N-(3-pyridinylmethyl)-ethanesulfonamide hydrochloride) were tested in mGlu2/3 agonist-sensitive rodent model(s) of anxiety and psychosis. As seen with LY354740, both 4-MPPTS and 4-APPES were efficacious in a rat fear-potentiated startle paradigm. Likewise in mice, CBiPES attenuated a stress-induced hyperthermia and PCP-induced hyperlocomotor activity. Furthermore, CBiPES mediated alteration in PCP-induced hyperlocomotor activity was sensitive to mGlu2/3 antagonist pretreatment. CONCLUSIONS: Taken together, the data indicate mGlu2 receptor potentiators have a unique use-dependent effect on presynaptic glutamate release, and show efficacy in several mGlu2/3-sensitive animal models of psychiatric disorders.
Subject(s)
Anxiety/drug therapy , Excitatory Amino Acid Agonists/pharmacology , Psychotic Disorders/drug therapy , Receptors, Metabotropic Glutamate/agonists , Synaptic Transmission/drug effects , Animals , Cyclopropanes/metabolism , Excitatory Postsynaptic Potentials/drug effects , Glycine/analogs & derivatives , Glycine/metabolism , Humans , Male , Mice , Mice, Inbred DBA , Mice, Inbred ICR , Motor Activity/drug effects , Phencyclidine/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Metabotropic Glutamate/physiologyABSTRACT
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
This report describes recently discovered novel allosteric modulators of metabotropic glutamate2 (mGlu2) receptors. These pyridylmethylsulfonamides (e.g., 3) potentiate glutamate, shifting agonist potency by 2-fold. This effect was specific for mGlu2 (vs mGlu1,3-8 receptors). Also, 3 failed to potentiate a chimeric mGlu2/1 receptor, demonstrating the mGlu2 transmembrane region's critical involvement. In a fear-potentiated startle model, 3 showed anxiolytic activity that was prevented by mGlu2/3 antagonist pretreatment. Thus, these pyridylmethylsulfonamides represent the first mGlu2 receptor potentiators discovered.
Subject(s)
Anti-Anxiety Agents/chemical synthesis , Pyridines/chemical synthesis , Receptors, Metabotropic Glutamate/drug effects , Sulfonamides/chemical synthesis , Allosteric Regulation , Animals , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacology , Calcium/metabolism , Cells, Cultured , Drug Synergism , Excitatory Amino Acid Agonists/pharmacology , Humans , Kinetics , Pyridines/chemistry , Pyridines/pharmacology , Rats , Receptors, Metabotropic Glutamate/agonists , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Reflex, Startle/drug effects , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
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. Diazepam (0.3, 0.6, and 1.0 mg/kg ip) attenuated both pre- and post-fear conditioning startle responses in a dose-related manner. In contrast, LY354740 (0.03, 0.3, and 3.0 mg/kg ip) did not disrupt preconditioning startle responses at doses that attenuated post-fear conditioning responses. The benzodiazepine antagonist, flumazenil, at a dose (2 mg/kg sc) that did not alter fear-potentiated startle per se, selectively reversed suppression of fear responses to diazepam (0.6 mg/kg ip) while not affecting fear suppression induced by LY354740 (0.3 mg/kg ip). At a dose of 1 mg/kg ip, the mGlu2/3 receptor antagonist, LY341495, did not disrupt fear-enhanced startle per se, but completely reversed the postconditioning anxiolytic effects of LY354740 in this model. This dose of LY341495 had no effect on fear suppression by diazepam. These results demonstrate that fear suppression by diazepam and LY354740 involves different neuronal mechanisms. While diazepam acts via the facilitation of GABAergic transmission, LY354740 induces its actions via the glutamatergic system, specifically mGlu2/3 receptor activation. Furthermore, in contrast to disruption of fear conditioning as well as fear suppression by diazepam, LY354740 had selective effects on fear expression, suggesting anxiolytic actions without the associated memory impairment.