ABSTRACT
Schizophrenia is a chronic, severe and highly complex mental illness. Current treatments manage the positive symptoms, yet have minimal effects on the negative and cognitive symptoms, two prominent features of the disease with critical impact on the long-term morbidity. In addition, antipsychotic treatments trigger serious side effects that precipitate treatment discontinuation. Here, we show that activation of the trace amine-associated receptor 1 (TAAR1), a modulator of monoaminergic neurotransmission, represents a novel therapeutic option. In rodents, activation of TAAR1 by two novel and pharmacologically distinct compounds, the full agonist RO5256390 and the partial agonist RO5263397, blocks psychostimulant-induced hyperactivity and produces a brain activation pattern reminiscent of the antipsychotic drug olanzapine, suggesting antipsychotic-like properties. TAAR1 agonists do not induce catalepsy or weight gain; RO5263397 even reduced haloperidol-induced catalepsy and prevented olanzapine from increasing body weight and fat accumulation. Finally, TAAR1 activation promotes vigilance in rats and shows pro-cognitive and antidepressant-like properties in rodent and primate models. These data suggest that TAAR1 agonists may provide a novel and differentiated treatment of schizophrenia as compared with current medication standards: TAAR1 agonists may improve not only the positive symptoms but also the negative symptoms and cognitive deficits, without causing adverse effects such as motor impairments or weight gain.
Subject(s)
Antipsychotic Agents/therapeutic use , Body Weight/drug effects , Depression/drug therapy , Receptors, G-Protein-Coupled/agonists , Schizophrenia/complications , Schizophrenia/drug therapy , Analysis of Variance , Animals , Antipsychotic Agents/pharmacology , Attention/drug effects , Attention/physiology , Benzodiazepines/therapeutic use , Cocaine/administration & dosage , Conditioning, Operant/drug effects , Depression/etiology , Disease Models, Animal , Dopamine Uptake Inhibitors/administration & dosage , Electroencephalography , Hallucinogens/toxicity , Haloperidol/adverse effects , Humans , Macaca fascicularis , Magnetic Resonance Imaging , Male , Mental Recall/drug effects , Mice , Mice, Inbred C57BL , Mice, Transgenic , Microinjections , Motor Activity/drug effects , Motor Activity/genetics , Mutation , Olanzapine , Oocytes , Oxazoles/pharmacokinetics , Phencyclidine/toxicity , Phenethylamines/pharmacokinetics , Protein Binding/drug effects , Protein Binding/genetics , Pyrrolidinones/administration & dosage , Rats , Rats, Wistar , Receptors, G-Protein-Coupled/genetics , Reinforcement, Psychology , Schizophrenia/etiology , Schizophrenia/genetics , Swimming/psychology , Telemetry , Tritium/pharmacokinetics , XenopusABSTRACT
BACKGROUND AND PURPOSE: As baclofen is active in patients with anxiety disorders, GABAB receptors have been implicated in the modulation of anxiety. To avoid the side effects of baclofen, allosteric enhancers of GABAB receptors have been studied to provide an alternative therapeutic avenue for modulation of GABAB receptors. The aim of this study was to characterize derivatives of (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF) as enhancers of GABAB receptors. EXPERIMENTAL APPROACH: Enhancing properties of rac-BHFF were assessed in the Chinese hamster ovary (CHO)-Galpha16-hGABA(B1a,2a) cells by Fluorometric Imaging Plate Reader and GTPgamma[35S]-binding assays, and in rat hippocampal slices by population spike (PS) recordings. In vivo activities of rac-BHFF were assessed using the loss of righting reflex (LRR) and stress-induced hyperthermia (SIH) models. KEY RESULTS: In GTPgamma[35S]-binding assays, 0.3 microM rac-BHFF or its pure enantiomer (+)-BHFF shifted the GABA concentration-response curve to the left, an effect that resulted in a large increase in both GABA potency (by 15.3- and 87.3-fold) and efficacy (149% and 181%), respectively. In hippocampal slices, rac-BHFF enhanced baclofen-induced inhibition of PS of CA1 pyramidal cells. In an in vivo mechanism-based model in mice, rac-BHFF increased dose-dependently the LRR induced by baclofen with a minimum effective dose of 3 mg kg(-1) p.o. rac-BHFF (100 mg kg(-1) p.o.) tested alone had no effect on LRR nor on spontaneous locomotor activity, but exhibited anxiolytic-like activity in the SIH model in mice. CONCLUSIONS AND IMPLICATIONS: rac-BHFF derivatives may serve as valuable pharmacological tools to elucidate the pathophysiological roles played by GABAB receptors in the central and peripheral nervous systems.
Subject(s)
Anti-Anxiety Agents/pharmacology , Benzofurans/pharmacology , Receptors, GABA-B/drug effects , Allosteric Regulation/drug effects , Animals , Anti-Anxiety Agents/administration & dosage , Anti-Anxiety Agents/chemistry , Baclofen/adverse effects , Baclofen/pharmacology , Benzofurans/administration & dosage , Benzofurans/chemistry , CHO Cells , Cricetinae , Cricetulus , Dose-Response Relationship, Drug , GABA Agonists/adverse effects , GABA Agonists/pharmacology , GTP-Binding Protein gamma Subunits/metabolism , Humans , Male , Mice , Mice, Inbred DBA , Pyramidal Cells/drug effects , Pyramidal Cells/metabolism , Rats , Rats, Wistar , Receptors, GABA-B/metabolism , Reflex/drug effects , StereoisomerismABSTRACT
The normal plasma protein serum amyloid P component (SAP) binds to fibrils in all types of amyloid deposits, and contributes to the pathogenesis of amyloidosis. In order to intervene in this process we have developed a drug, R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid, that is a competitive inhibitor of SAP binding to amyloid fibrils. This palindromic compound also crosslinks and dimerizes SAP molecules, leading to their very rapid clearance by the liver, and thus produces a marked depletion of circulating human SAP. This mechanism of drug action potently removes SAP from human amyloid deposits in the tissues and may provide a new therapeutic approach to both systemic amyloidosis and diseases associated with local amyloid, including Alzheimer's disease and type 2 diabetes.
