Aporphinoid Antagonists of 5‐HT_2A Receptors: Further Evaluation of Ring A Substituents and the Size of Ring C

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 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.

Mechanism Exploration of Arylpiperazine Derivatives Targeting the 5-HT2A Receptor by In Silico Methods

“…By a combinatorial study using both the docking and MD analyses, as well as a detailed comparison between these results, it is demonstrated that the present docking model is reliable in reflecting the particular binding mechanism in the 5-HT 2A receptor active site. To further explore the interaction features of general 5-HT 2A antagonists and the binding model of arylpiperazine derivatives with the target protein, a comparison of previously-reported docking studies of known 5-HT 2A antagonists with the ones assessed in our current work was conducted [ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]. Above Table 2 summarizes the important information obtained from these studies, for purpose to compare their similarities and differences, with their representative structures of the ligands summarized in Figure 10 .…”

“…Due to that an accurate 3D structure of the receptor is essential for docking analysis, and until now an X-ray structure of 5-HT 2A receptor is, yet, still unavailable, the homology modeling becomes a necessity in the present work. In addition, since, to our best knowledge, almost all (which is actually, 7 out of 9 as shown in Table 2 ) current crystal structures of 5-HT 2A receptor built by homology modeling for further docking analysis were based on the structure of β 2 -adrenergic receptor as a template [ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ], for purpose of a well comparison with previously-reported docking studies of known 5-HT 2A antagonists, the structure of 5-HT 2A receptor we used presently still adopted the structure of β 2 -adrenergic receptor as the homology modeling’s template. Actually, this structure was built by Ísberg et al, where the 5-HT 2A receptor model was constructed using the β 2 -adrenergic receptor (PDB entry 2RH1) as the main template, and then further modified to incorporate template features from the active G-protein-bound opsin crystal structure (PDB entry 3DQB) [ 47 ].…”

C4 phenyl aporphines with selective h5-HT2B receptor affinity

“…15–17 The 5-HT 2A receptor plays a significant role in various neuropsychiatric disorders such as schizophrenia, anxiety depression and psychostimulant abuse. 18–22 Selective 5-HT 2A antagonists are being pursued as novel therapeutics to treat sleep disorders.…”

Synthesis and evaluation of aporphine analogs containing C1 allyl isosteres at the h5-HT2A receptor

“…In that context, our previous SAR studies based on the aporphine alkaloid nantenine ( 4 , Figure 2) have resulted in the identification of new aporphinoid 5-HT 2A receptor antagonists with significantly improved affinity and selectivity as compared to nantenine. 10-13 In continuing efforts in that vein, we wish to report an SAR study that has resulted in the identification of the most potent aporphine-derived 5-HT 2A receptor antagonist known to date.…”

“…11,13,14 These studies have shown that substituents at the C1 position of nantenine may be manipulated to improve 5-HT 2A affinity and selectivity. n -Alkyl substituents were particularly well tolerated.…”