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Aporphinoid Antagonists of 5‐ HT 2A Receptors: Further Evaluation of Ring A Substituents and the Size of Ring C
Author(s) -
Ponnala Shashikanth,
Kapadia Nirav,
Navarro Hernán A.,
Harding Wayne W.
Publication year - 2014
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12345
Subject(s) - moiety , chemistry , antagonist , stereochemistry , receptor , halogenation , potency , ring (chemistry) , biochemistry , in vitro , organic chemistry
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‐ HT 2A and α 1A receptors. Halogenation improves 5‐HT 2A antagonist potency in molecules containing a C 1 methoxyl/C2 methoxyl or C1 methoxyl/C2 hydroxyl moiety. Bromination or iodination (but not chlorination) with the latter moiety also significantly increased α 1A 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.