ABSTRACT
A pharmacophore model for triple reuptake inhibitors and the new class of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes were recently reported. Further investigation in this area led to the identification of a new series of potent and selective triple reuptake inhibitors endowed with good developability characteristics. Excellent bioavailability and brain penetration are associated with this series of 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptanes together with high in vitro potency and selectivity at SERT, NET, and DAT. In vivo microdialysis experiments in different animal models and receptor occupancy studies in rat confirmed that derivative 17 showed an appropriate profile to guarantee further progression of the compound.
Subject(s)
Depressive Disorder/drug therapy , Heptanes/chemistry , Heptanes/pharmacology , Neurotransmitter Uptake Inhibitors/chemistry , Neurotransmitter Uptake Inhibitors/pharmacology , Animals , Antidepressive Agents/chemical synthesis , Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Azabicyclo Compounds/chemical synthesis , Azabicyclo Compounds/chemistry , Azabicyclo Compounds/pharmacology , Brain/metabolism , Depressive Disorder/metabolism , Dopamine/metabolism , Heptanes/chemical synthesis , Humans , Magnetic Resonance Spectroscopy , Male , Mass Spectrometry , Mice , Microdialysis , Models, Molecular , Neurotransmitter Uptake Inhibitors/chemical synthesis , Norepinephrine/metabolism , Rats , Rats, Sprague-Dawley , Serotonin/metabolism , Structure-Activity RelationshipABSTRACT
The discovery of new highly potent and selective triple reuptake inhibitors is reported. The new classes of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes are described together with detailed SAR. Appropriate decoration of the scaffolds was achieved with the help of a triple reuptake inhibitor pharmacophore model detailed here. Selected derivatives showed good oral bioavailability (>30%) and brain penetration (B/B > 4) in rats associated with high in vitro potency and selectivity at SERT, NET, and DAT. Among these compounds, microdialysis and in vivo experiments confirm that derivative 15 has an appropriate developability profile to be considered for further progression.
Subject(s)
Azabicyclo Compounds/pharmacology , Dopamine Plasma Membrane Transport Proteins/antagonists & inhibitors , Norepinephrine Plasma Membrane Transport Proteins/antagonists & inhibitors , Serotonin Plasma Membrane Transport Proteins/metabolism , Animals , Azabicyclo Compounds/chemistry , Azabicyclo Compounds/pharmacokinetics , Binding, Competitive , Biogenic Monoamines/metabolism , Biological Availability , Biological Transport/drug effects , Cell Line , Chromatography, High Pressure Liquid , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Dopamine Plasma Membrane Transport Proteins/metabolism , Humans , Male , Mice , Microdialysis , Microsomes, Liver/metabolism , Models, Chemical , Molecular Structure , Motor Activity/drug effects , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Prefrontal Cortex/metabolism , Rats , Structure-Activity RelationshipABSTRACT
The present study compared the effects of two selective dopamine (DA) D(3) receptor antagonists, SB-277011A (3, 10 and 30 mg/kg i.p.) and SB-414796A (3, 10 and 30 mg/kg i.p.) on extracellular levels of acetylcholine (ACh) in the rat medial prefrontal cortex (mPFC) by using a LC/MS-MS analytical method that permitted the detection of ACh without the necessity of adding acetylcholinesterase inhibitors to the perfusate. Furthermore, the present LC/MS-MS method permitted the simultaneous measurement of the respective concentrations of SB-277011A and SB-414796A in the same extracellular samples from the mPFC. The systemic administration of both selective DA D(3) receptor antagonists produced a significant increase in extracellular levels of Ach compared to vehicle-treated animals, which was associated with increases in extracellular concentrations of SB-277011A and SB-414796. Overall, the present findings further strengthen the likelihood of a modulation of cortical cholinergic function through a DA D(3)-mediated mechanism and suggest that selective DA D(3) receptor antagonism may be beneficial in the treatment of psychiatric diseases, such as schizophrenia, which are characterized by cognitive dysfunction.
Subject(s)
Acetylcholine/metabolism , Anticholesteremic Agents/pharmacology , Chromatography, High Pressure Liquid/methods , Dopamine Antagonists/pharmacology , Mass Spectrometry/methods , Prefrontal Cortex/drug effects , Animals , Brain Chemistry/drug effects , Dose-Response Relationship, Drug , Drug Interactions , Extracellular Space/drug effects , Heterocyclic Compounds, 2-Ring/pharmacology , Male , Microdialysis/methods , Oxadiazoles/pharmacology , Rats , Rats, Sprague-DawleyABSTRACT
Aripiprazole, a novel atypical antipsychotic drug, can significantly increase dopamine (DA) levels in the prefrontal cortex of rats, but only at low doses below 1mg/kg. The aim of the present work was to test the effect of aripiprazole (0, 0.1, 0.3, 3 and 30 mg/kg, i.p.) on extracellular levels of monoamines in the prefrontal cortex of freely moving C57BL/6J mice. Concurrent horizontal locomotor activity was also assessed. Aripiprazole produced a significant increase in dialysate DA levels after the administration of a low dose of 0.3mg/kg. Lower (0.1 mg/kg) or higher (3 and 30 mg/kg) doses failed to affect extracellular levels of DA. In addition, none of the doses tested in the present study produced significant changes in extracellular levels of noradrenaline (NA) and serotonin (5-HT). For the sake of comparison, clozapine (0, 3 and 10 mg/kg, s.c.) was also tested under similar conditions. Clozapine produced a dose-dependent increase in both dialysate DA and NA levels without affecting extracellular 5-HT. Locomotor activity was significantly decreased by both clozapine and aripiprazole. These data further support the hypothesis that selective activation of dopaminergic neurotransmission in the prefrontal cortex may contribute to the therapeutic efficacy of aripiprazole.
Subject(s)
Dopamine/metabolism , Piperazines/pharmacology , Prefrontal Cortex/drug effects , Quinolones/pharmacology , Up-Regulation/drug effects , Animals , Antipsychotic Agents/pharmacology , Aripiprazole , Clozapine/pharmacology , Dose-Response Relationship, Drug , Extracellular Fluid/drug effects , Extracellular Fluid/metabolism , Male , Mice , Mice, Inbred C57BL , Microdialysis , Motor Activity/drug effects , Motor Activity/physiology , Norepinephrine/metabolism , Prefrontal Cortex/metabolism , Serotonin/metabolism , Synaptic Transmission/drug effects , Synaptic Transmission/physiology , Up-Regulation/physiologyABSTRACT
The existence of subterritories within the nucleus accumbens has now been widely supported by histochemical, neurochemical, electrophysiological, as well as morphological and ultrastructural studies and suggest specific afferent and efferent systems involved in different behavioral aspects. Microdialysis studies in the rat have consistently shown that most drugs of abuse increase extracellular dopamine levels preferentially in the shell subregion of the nucleus accumbens. The study of the relative roles of NAc subregions may considerably help our understanding of the neurobiological basis of drug addiction. Accordingly, the aim of the present work was to extend the outcome of rat studies to the mouse species. Five major drugs of abuse were systemically and acutely administered to mice with a microdialysis probe implanted in either the shell or the core. A statistical comparison was performed on data transformed as percentage values of baseline dopamine vs. logarithmic values with baseline dopamine as a covariate. Results show a significant increase in dopamine levels in both the shell and core subregions following cocaine, amphetamine, nicotine, ethanol, and morphine treatments. A difference between shell and core after cocaine, nicotine, and morphine was evident when data were analyzed as percent values of baseline. However, such a shell-core dichotomy became no longer significant when ANOVA was applied on the statistically more appropriate logarithmic transformation of data with baseline as a covariate. The significant baseline differences among groups of mice (dopamine levels in the shell significantly lower compared with dopamine levels in the core) may have compromised, at least in part, the statistical procedure usually applied in microdialysis studies. These findings suggest that a careful evaluation of the data is required when subtle changes in extracellular levels of DA are measured.
Subject(s)
Dopamine/metabolism , Illicit Drugs/pharmacology , Nucleus Accumbens/drug effects , Substance-Related Disorders/metabolism , Amphetamine/administration & dosage , Amphetamine/pharmacology , Anesthetics, Local/administration & dosage , Anesthetics, Local/pharmacology , Animals , Calbindins , Central Nervous System Depressants , Central Nervous System Stimulants/pharmacology , Cocaine/administration & dosage , Cocaine/pharmacology , Disease Models, Animal , Ethanol/administration & dosage , Ethanol/pharmacology , Extracellular Space/metabolism , Immunohistochemistry , Male , Mice , Microdialysis/methods , Morphine/administration & dosage , Morphine/pharmacology , Narcotics/administration & dosage , Narcotics/pharmacology , Nicotine/administration & dosage , Nicotine/pharmacology , Nicotinic Agonists/administration & dosage , Nicotinic Agonists/pharmacology , Nucleus Accumbens/metabolism , S100 Calcium Binding Protein G/metabolism , Time FactorsABSTRACT
We tested fluoxetine, bupropion and GR 205171, a selective neurokinin-1 receptor antagonist on forced swimming test (FST) response and on levels of monoamines in frontal cortex of CD1 mice by microdialysis techniques. All drugs decreased immobility time. Fluoxetine augmented all monoamines, bupropion enhanced catecholamines, and GR 205171 was totally ineffective. Results suggest that FST response may not be related to levels of monoamines in the mouse frontal cortex.
