ABSTRACT
Further exploration around the recently disclosed potent triple re-uptake inhibitor 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane led to the identification of a new series of potent triple re-uptake inhibitors endowed with good developability characteristics. The insertion of a further aryl moiety into the template allowed the 'titration' of the SERT/NET/DAT ratio leading to the identification of further tools in this important area.
Subject(s)
Adrenergic Uptake Inhibitors/chemistry , Dopamine Uptake Inhibitors/chemistry , Heptanes/chemistry , Selective Serotonin Reuptake Inhibitors/chemistry , Adrenergic Uptake Inhibitors/chemical synthesis , Adrenergic Uptake Inhibitors/pharmacology , Aza Compounds/chemistry , Bridged Bicyclo Compounds/chemistry , Dopamine Plasma Membrane Transport Proteins/chemistry , Dopamine Plasma Membrane Transport Proteins/metabolism , Dopamine Uptake Inhibitors/chemical synthesis , Dopamine Uptake Inhibitors/pharmacology , Heptanes/chemical synthesis , Heptanes/pharmacology , Humans , Norepinephrine Plasma Membrane Transport Proteins/chemistry , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Protein Binding , Serotonin Plasma Membrane Transport Proteins/chemistry , Serotonin Plasma Membrane Transport Proteins/metabolism , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
A new class of azabicyclo[3.1.0]benzenesulfonamides is presented as selective dopamine D3 antagonists together with SAR and selectivity data.
Subject(s)
Dopamine Antagonists/chemistry , Dopamine Antagonists/pharmacology , Receptors, Dopamine D3/antagonists & inhibitors , Receptors, Dopamine D3/metabolism , Sulfonamides/chemistry , Sulfonamides/pharmacology , Benzene/chemistry , Benzene/pharmacology , Humans , Structure-Activity RelationshipABSTRACT
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
Herein we report a detailed description of the structure-activity relationships for a novel series of "C-linked" 1,2,4-triazolylazabicyclo[3.1.0]hexanes. These derivatives are endowed with very high in vitro affinity and selectivity for the dopamine D(3) receptor. An optimization with respect to undesired affinity toward the hERG potassium channel is also reported. Members of this compound series also show excellent in vitro and in vivo pharmacokinetic properties.
Subject(s)
Aza Compounds/chemistry , Bridged Bicyclo Compounds/chemistry , Hexanes/chemistry , Receptors, Dopamine D3/antagonists & inhibitors , Triazoles/chemistry , Animals , Binding Sites , Computer Simulation , Hexanes/chemical synthesis , Hexanes/pharmacokinetics , Humans , Rats , Receptors, Dopamine D3/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 discovery of new highly potent and selective dopamine (DA) D(3) receptor antagonists has recently allowed the characterization of the DA D(3) receptor in a range of preclinical animal models of drug addiction. A novel series of 1,2,4-triazol-3-yl-azabicyclo[3.1.0]hexanes, members of which showed a high affinity and selectivity for the DA D(3) receptor and excellent pharmacokinetic profiles, is reported here. Members of a group of derivatives from this series showed good oral bioavailability and brain penetration and very high in vitro affinity and selectivity for the DA D(3) receptor, as well as high in vitro potency for antagonism at this receptor. Several members of this series also significantly attenuate the expression of conditioned place preference (CPP) to nicotine and cocaine.
Subject(s)
Hexanes/chemistry , Hexanes/pharmacology , Receptors, Dopamine D3/antagonists & inhibitors , Animals , Cell Membrane/drug effects , Cell Membrane/metabolism , Computer Simulation , Drug Design , Guinea Pigs , Humans , Male , Models, Animal , Models, Chemical , Molecular Structure , Receptors, Dopamine D3/biosynthesis , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The lead optimization process to identify new selective dopamine D(3) receptor antagonists is reported. DMPK parameters and binding data suggest that selective D(3) receptor antagonists as potential PET ligands might have been identified.
Subject(s)
Imidazolidines/chemistry , Receptors, Dopamine D3/antagonists & inhibitors , Animals , Brain/drug effects , Chemistry, Organic/methods , Chemistry, Pharmaceutical/methods , Dopamine D2 Receptor Antagonists , Humans , Imidazolidines/chemical synthesis , Imidazolidines/pharmacology , Inhibitory Concentration 50 , Ligands , Models, Chemical , Positron-Emission Tomography , Rats , Receptors, Dopamine D2/metabolism , Receptors, Dopamine D3/metabolism , Structure-Activity Relationship , SwineABSTRACT
The synthesis and SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported. The introduction of a tricyclic [h]-fused benzazepine moiety on the recently disclosed scaffold of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines is reported. A full rat pharmacokinetic characterization is also reported.
Subject(s)
Benzazepines/chemical synthesis , Benzazepines/pharmacology , Dopamine Antagonists/chemical synthesis , Dopamine Antagonists/pharmacology , Receptors, Dopamine D3/antagonists & inhibitors , Animals , Benzazepines/chemistry , Combinatorial Chemistry Techniques , Dopamine Antagonists/chemistry , Drug Design , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
The synthesis and the SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported. The new scaffolds of the [g]-fused and the hetero-fused tricyclic benzazepine are here reported together with their pharmacokinetic profile.
Subject(s)
Benzazepines/chemical synthesis , Benzazepines/pharmacology , Dopamine Antagonists/chemical synthesis , Dopamine Antagonists/pharmacology , Receptors, Dopamine D3/antagonists & inhibitors , Animals , Benzazepines/chemistry , Combinatorial Chemistry Techniques , Dopamine Antagonists/chemistry , Drug Design , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
The discovery of new highly potent and selective dopamine D3 receptor antagonists has recently permitted characterization of the role of the dopamine D3 receptor in a wide range of preclinical animal models. A novel series of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines demonstrating a high level of D3 affinity and selectivity with an excellent pharmacokinetic profile is reported here. In particular, the pyrazolyl derivative 35 showed good oral bioavailability and brain penetration associated with high potency and selectivity in vitro. In vivo characterization of 35 confirmed that this compound blocks the expression of nicotine- and cocaine-conditioned place preference in the rat, prevents nicotine-triggered reinstatement of nicotine-seeking behavior in the rat, reduces oral operant alcohol self-administration in the mouse, increases extracellular levels of acetylcholine in the rat medial prefrontal cortex, and potentiates the amplitude of the relative cerebral blood volume response to d-amphetamine in a regionally specific manner in the rat brain.
Subject(s)
Benzazepines/chemical synthesis , Receptors, Dopamine D3/antagonists & inhibitors , Triazoles/chemical synthesis , Acetylcholine/metabolism , Administration, Oral , Alcohol Drinking/prevention & control , Animals , Benzazepines/pharmacokinetics , Benzazepines/pharmacology , Brain/blood supply , Brain/metabolism , Cocaine/pharmacology , Conditioning, Operant/drug effects , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/metabolism , Guinea Pigs , Histamine H1 Antagonists/chemical synthesis , Histamine H1 Antagonists/pharmacokinetics , Histamine H1 Antagonists/pharmacology , Humans , In Vitro Techniques , Male , Mice , Mice, Inbred C57BL , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Models, Molecular , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D3/agonists , Receptors, Histamine H1/metabolism , Structure-Activity Relationship , Tobacco Use Disorder/prevention & control , Triazoles/pharmacokinetics , Triazoles/pharmacologyABSTRACT
Two new classes of potent and selective CRF(1) receptor antagonists are presented. Exploration of general templates 3 and 4 through modifications of the top amine and bottom phenyl substituents led to optimization of the in vitro affinity and pharmacokinetic profiles. The typical alkyl chains present in the top region of CRF(1) antagonists were replaced by substituted heteroaryl moieties, leading to a dramatic improvement of the metabolic stability. This improvement was apparent when the compounds were dosed in vivo: several compounds exhibited low plasma clearance, good oral bioavailability, and high brain penetration. As a consequence of their outstanding pharmacokinetic profiles, these CRF(1) antagonists, as exemplified by compound 4 fi (4-(4-bromo-3-methyl-1H-pyrazol-1-yl)-7-(2,4-dichlorophenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine), produced a dose-dependent "anxiolytic-like" effect when administered orally, decreasing the vocalization of rat pups.
Subject(s)
Pyrimidines/chemistry , Pyrimidines/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacology , Dose-Response Relationship, Drug , Microsomes, Liver/metabolism , Models, Molecular , Molecular Structure , Protein Binding , Pyrimidines/metabolism , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Vocalization, Animal/drug effectsABSTRACT
Within the continuous quest for the discovery of novel compounds able to treat anxiety and depression, the generation of a pharmacophore model for 5-HT2C receptor antagonists and the discovery of a new class of potent and selective 5-HT2C molecules are reported.
