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C4 phenyl aporphines with selective h5-HT(2B) receptor affinity
Nirav Kapadia1, Wayne W Harding1
1Chemistry Dept., Hunter College, CUNY, 695 Park Avenue, NY 10065, USA; The Graduate Center, City University of New York, 365 5th Avenue, NY 10016, USA.
Bioorganic & Medicinal Chemistry Letters
|August 1, 2015
Summary
New aporphine alkaloids were synthesized and tested for serotonin receptor affinity. Most analogs selectively bind to the serotonin 5-HT(2B) receptor, with compound 5a showing the highest affinity as an antagonist.
Area of Science:
- Medicinal Chemistry
- Neuropharmacology
- Organic Synthesis
Background:
- Aporphine alkaloids, including nantenine, are known to interact with serotonin receptors.
- Understanding structure-activity relationships is crucial for developing selective receptor ligands.
Purpose of the Study:
- To synthesize novel aporphine alkaloid analogs with modifications at C1 and N positions.
- To evaluate the affinity of these analogs for various human serotonin (5-HT) receptors.
- To identify selective ligands for specific 5-HT receptor subtypes.
Main Methods:
- Synthesis of a series of aporphine alkaloids based on the nantenine scaffold.
- Radioligand binding assays to determine receptor affinity for human 5-HT receptors (e.g., 5-HT(2A), 5-HT(2B)).
- Evaluation of selectivity against other central nervous system (CNS) receptors.
Main Results:
- The synthesized analogs generally lacked affinity for the 5-HT(2A) and other 5-HT receptors.
- A selective binding profile for the 5-HT(2B) receptor was observed for most analogs.
- Bulky substituents at C1 or N positions reduced 5-HT(2B) receptor affinity when a C4 phenyl group was present.
- Compound 5a exhibited the highest 5-HT(2B) receptor affinity and acted as an antagonist, with selectivity over other CNS receptors.
Conclusions:
- Novel aporphine alkaloid analogs were developed with a distinct serotonin receptor binding profile.
- These compounds demonstrate potential as selective 5-HT(2B) receptor ligands.
- Compound 5a is a promising selective 5-HT(2B) receptor antagonist for further investigation.