5-HT2C antagonists based on fused heterotricyclic templates: design, synthesis and biological evaluation.
Design, synthesis and properties of a new tricyclic series of selective 5-HT2C receptor antagonists are reported. Conformational analysis of a 2-phenyl-dihydropyrrolone scaffold suggested that ring fusion, locking coplanarity between the rings of this moiety, might be tolerated by the 5-HT2C receptor. An interesting effect of this is the change of the nature of the carbon-carbon double bond of the lactam ring from vinylic to aromatic. The changes were found to result in a favourable profile at both, receptor and in vivo level.
Hamprecht
Dieter
D
GlaxoSmithKline, Medicine Research Centre, Via Fleming, 4, 37135 Verona, Italy. dieter.w.hamprecht@gsk.com
Micheli
Fabrizio
F
Tedesco
Giovanna
G
Donati
Daniele
D
Petrone
Marcella
M
Terreni
Silvia
S
Wood
Martyn
M
D000478:Alkylation; D000818:Animals; D001682:Biological Availability; D015195:Drug Design; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007202:Indicators and Reagents; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects; D044403:Receptor, Serotonin, 5-HT2B / Q000187:drug effects; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D006571:Heterocyclic Compounds; D007202:Indicators and Reagents; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D012702:Serotonin Antagonists