Aporphinoid antagonists of 5-HT2A receptors: further evaluation of ring A substituents and the size of ring C.
A series of ring A-modified analogs of nantenine as well as structural variants in ring C were synthesized and evaluated for antagonist activity at 5-HT2A and α1A receptors. Halogenation improves 5-HT2A antagonist potency in molecules containing a C1 methoxyl/C2 methoxyl or C1 methoxyl/C2 hydroxyl moiety. Bromination or iodination (but not chlorination) with the latter moiety also significantly increased α1A antagonist potency. Homologation or contraction of ring C adversely affected antagonist activity at both receptors, implying that a six-membered ring C motif is beneficial for high antagonist potency at both receptors. Molecular docking studies suggest that the improved antagonist activity (by virtue of improved affinity) of C3-halogenated aporphines in this study is attributable to favorable interactions with the C3 halogen and F339 and/or F340.
Chemistry Department, Hunter College, CUNY, 695 Park Avenue, NY, 10065, USA.
Shashikanth
S
Ponnala
Nirav
N
Kapadia
Hernán A
HA
Navarro
Wayne W
WW
Harding
D001060:Aporphines / Q000737:chemistry*; D060326:Chemistry Techniques, Synthetic; D062105:Molecular Docking Simulation; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D001060:Aporphines; D058830:Serotonin 5-HT2 Receptor Antagonists; C041615:nantenine
5-HT2A; antagonist; aporphine; nantenine; structure-activity relationship; α1A