Abstract
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.
MeSH terms
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Acetylcholine / metabolism
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Administration, Oral
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Alcohol Drinking / prevention & control
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Animals
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Benzazepines / chemical synthesis*
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Benzazepines / pharmacokinetics
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Benzazepines / pharmacology
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Brain / blood supply
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Brain / metabolism
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Cocaine / pharmacology
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Conditioning, Operant / drug effects
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels / metabolism
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Guinea Pigs
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Histamine H1 Antagonists / chemical synthesis
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Histamine H1 Antagonists / pharmacokinetics
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Histamine H1 Antagonists / pharmacology
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Humans
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In Vitro Techniques
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Male
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Mice
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Mice, Inbred C57BL
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Microsomes, Liver / drug effects
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Microsomes, Liver / metabolism
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Models, Molecular
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Radioligand Assay
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Rats
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Rats, Sprague-Dawley
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Receptors, Dopamine D3 / agonists
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Receptors, Dopamine D3 / antagonists & inhibitors*
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Receptors, Histamine H1 / metabolism
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Structure-Activity Relationship
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Tobacco Use Disorder / prevention & control
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Triazoles / chemical synthesis*
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Triazoles / pharmacokinetics
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Triazoles / pharmacology
Substances
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7-(1,3-dimethyl-1H-pyrazol-5-yl)-3-(3-((4-methyl-5-(2-methyl-5-quinolinyl)-4H-1,2,4-triazol-3-yl)thio)propyl)-2,3,4,5-tetrahydro-1H-3-benzazepine
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Benzazepines
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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Histamine H1 Antagonists
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Receptors, Dopamine D3
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Receptors, Histamine H1
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Triazoles
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Cocaine
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Acetylcholine