Abstract
A series of N-substituted (2-phenylcyclopropyl)methylamines were designed and synthesized, with the aim of finding serotonin 2C (5-HT2C)-selective agonists with a preference for Gq signaling. A number of these compounds exhibit 5-HT2C selectivity with a preference for Gq-mediated signaling compared with β-arrestin recruitment. Furthermore, the N-methyl compound (+)-15a, which displayed an EC50 of 23 nM in the calcium flux assay while showing no β-arrestin recruitment activity, is the most functionally selective 5-HT2C agonist reported to date. The N-benzyl compound (+)-19, which showed an EC50 of 24 nM at the 5-HT2C receptor, is fully selective over the 5-HT2B receptor. In an amphetamine-induced hyperactivity model, compound (+)-19 showed significant antipsychotic-drug-like activity. These novel compounds shed light on the role of functional selectivity at the 5-HT2C receptor with respect to antipsychotic activity.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antipsychotic Agents / chemical synthesis
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Antipsychotic Agents / chemistry*
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Antipsychotic Agents / pharmacology
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Benzylamines / chemical synthesis
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Benzylamines / chemistry*
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Benzylamines / pharmacology
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Cyclopropanes / chemical synthesis
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Cyclopropanes / chemistry*
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Cyclopropanes / pharmacology
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HEK293 Cells
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Humans
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Hyperkinesis / chemically induced
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Hyperkinesis / drug therapy
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Male
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Methylamines / chemical synthesis
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Methylamines / chemistry*
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Methylamines / pharmacology
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Mice, Inbred C57BL
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Receptor, Serotonin, 5-HT2B / metabolism
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Receptor, Serotonin, 5-HT2C / metabolism*
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Serotonin 5-HT2 Receptor Agonists / chemical synthesis
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Serotonin 5-HT2 Receptor Agonists / chemistry*
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Serotonin 5-HT2 Receptor Agonists / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
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beta-Arrestins / metabolism
Substances
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1-(2-(5-fluoro-2-methoxyphenyl)cyclopropyl)-N-(2-methoxybenzyl)methanamine
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Antipsychotic Agents
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Benzylamines
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Cyclopropanes
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Methylamines
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Receptor, Serotonin, 5-HT2B
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Receptor, Serotonin, 5-HT2C
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Serotonin 5-HT2 Receptor Agonists
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beta-Arrestins