Abstract
The discovery of a new series of compounds that are potent, selective 5-HT2C receptor agonists is described herein as we continue our efforts to optimize the 2-phenylcyclopropylmethylamine scaffold. Modifications focused on the alkoxyl substituent present on the aromatic ring led to the identification of improved ligands with better potency at the 5-HT2C receptor and excellent selectivity against the 5-HT2A and 5-HT2B receptors. ADMET studies coupled with a behavioral test using the amphetamine-induced hyperactivity model identified four compounds possessing drug-like profiles and having antipsychotic properties. Compound (+)-16b, which displayed an EC50 of 4.2 nM at 5-HT2C, no activity at 5-HT2B, and an 89-fold selectivity against 5-HT2A, is one of the most potent and selective 5-HT2C agonists reported to date. The likely binding mode of this series of compounds to the 5-HT2C receptor was also investigated in a modeling study, using optimized models incorporating the structures of β2-adrenergic receptor and 5-HT2B receptor.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Allyl Compounds / chemical synthesis
-
Allyl Compounds / chemistry
-
Allyl Compounds / pharmacology*
-
Amphetamine
-
Animals
-
Antipsychotic Agents / chemical synthesis
-
Antipsychotic Agents / chemistry
-
Antipsychotic Agents / pharmacology*
-
Caco-2 Cells
-
Cytochrome P-450 Enzyme System / metabolism
-
Dose-Response Relationship, Drug
-
Humans
-
Locomotion / drug effects*
-
Male
-
Methylamines / chemical synthesis
-
Methylamines / chemistry
-
Methylamines / pharmacology*
-
Mice
-
Mice, Inbred C57BL
-
Microsomes, Liver / drug effects
-
Microsomes, Liver / enzymology
-
Microsomes, Liver / metabolism
-
Models, Molecular
-
Molecular Structure
-
Receptor, Serotonin, 5-HT2C / metabolism*
-
Serotonin 5-HT2 Receptor Agonists / chemical synthesis
-
Serotonin 5-HT2 Receptor Agonists / chemistry
-
Serotonin 5-HT2 Receptor Agonists / pharmacology*
-
Structure-Activity Relationship
Substances
-
(2-(2-(allyloxy)-5-fluorophenyl)cyclopropyl)methanamine
-
Allyl Compounds
-
Antipsychotic Agents
-
Methylamines
-
Receptor, Serotonin, 5-HT2C
-
Serotonin 5-HT2 Receptor Agonists
-
Cytochrome P-450 Enzyme System
-
Amphetamine