Aporphinoid antagonists of 5-HT2A receptors: further evaluation of ring A substituents and the size of ring C.

Shashikanth Ponnala, Nirav Kapadia, Hernán A Navarro, Wayne W Harding

Chemical biology & drug design 2014 Nov

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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. © 2014 John Wiley & Sons A/S.

Citation

Shashikanth Ponnala, Nirav Kapadia, Hernán A Navarro, Wayne W Harding. Aporphinoid antagonists of 5-HT2A receptors: further evaluation of ring A substituents and the size of ring C. Chemical biology & drug design. 2014 Nov;84(5):558-66