• Journal Article

Aporphinoid Antagonists of 5-HT2A Receptors: Further Evaluation of Ring A Substituents and the Size of Ring C

Citation

Ponnala, S., Kapadia, N., Navarro, H., & Harding, W. W. (2014). Aporphinoid Antagonists of 5-HT2A Receptors: Further Evaluation of Ring A Substituents and the Size of Ring C. Chemical Biology & Drug Design, 84(5), 558-566. DOI: 10.1111/cbdd.12345

Abstract

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 (1A) 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 (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