Abstract
We report the synthesis and structure-activity relationships of a class of tetracyclic butyrophenones that exhibit potent binding affinities to serotonin 5-HT(2A) and dopamine D2 receptors. This work has led to the discovery of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluorophenyl)-butan-1-one 4-methylbenzenesulfonate (ITI-007), which is a potent 5-HT(2A) antagonist, postsynaptic D2 antagonist, and inhibitor of serotonin transporter. This multifunctional drug candidate is orally bioavailable and exhibits good antipsychotic efficacy in vivo. Currently, this investigational new drug is under clinical development for the treatment of neuropsychiatric and neurological disorders.
MeSH terms
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Adrenergic Uptake Inhibitors / chemical synthesis
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Adrenergic Uptake Inhibitors / pharmacology
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Animals
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Behavior, Animal / drug effects
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Biological Availability
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Drug Discovery
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Electroshock
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Indicators and Reagents
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Male
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Mental Disorders / drug therapy*
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Nervous System Diseases / drug therapy*
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Quinoxalines / chemical synthesis*
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Quinoxalines / pharmacokinetics
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Quinoxalines / pharmacology*
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Quipazine / pharmacology
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Rats
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Rats, Sprague-Dawley
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Receptor, Serotonin, 5-HT2A / chemistry
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Receptor, Serotonin, 5-HT2A / drug effects
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Receptor, Serotonin, 5-HT2A / metabolism
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Receptors, Dopamine D2 / chemistry
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Receptors, Dopamine D2 / drug effects
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Receptors, Dopamine D2 / metabolism
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Recombinant Proteins / drug effects
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Schizophrenia / drug therapy
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Serotonin Antagonists / chemical synthesis
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Serotonin Antagonists / pharmacology
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Serotonin Plasma Membrane Transport Proteins / drug effects
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Structure-Activity Relationship
Substances
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Adrenergic Uptake Inhibitors
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Indicators and Reagents
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Quinoxalines
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Receptor, Serotonin, 5-HT2A
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Receptors, Dopamine D2
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Recombinant Proteins
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Serotonin Antagonists
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Serotonin Plasma Membrane Transport Proteins
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Quipazine