A new class of 5‐HT_2A/5‐HT_2C receptor inverse agonists: Synthesis, molecular modeling, in vitro and in vivo pharmacology of novel 2‐aminotetralins

Abstract

Background and Purpose The 5‐HT receptor subtypes 5‐HT2A and 5‐HT2C are important neurotherapeutic targets, though, obtaining selectivity over 5‐HT2B and H1 receptors is challenging. Here, we delineated molecular determinants of selective binding to 5‐HT2A and 5‐HT2C receptors for novel 4‐phenyl‐2‐dimethylaminotetralins (4‐PATs). Experimental Approach We synthesized 42 novel 4‐PATs with halogen or aryl moieties at the C(4)‐phenyl meta‐position. Affinity, function, molecular modeling and 5‐HT2A receptor mutagenesis studies were performed to understand structure–activity relationships at 5‐HT2‐type and H1 receptors. Lead 4‐PAT‐type 5‐HT2A/5‐HT2C receptor inverse agonists were compared with pimavanserin, a selective 5‐HT2A/5‐HT2C receptor inverse agonist approved to treat Parkinson's disease‐related psychosis, in the mouse head twitch response and locomotor activity assays, models relevant to antipsychotic drug development. Key Results Most 4‐PAT diastereomers in the (2S,4R)‐configuration bound non‐selectively to 5‐HT2A, 5‐HT2C and H1 receptors, with >100‐fold selectivity over 5‐HT2B receptors, whereas diastereomers in the (2R,4R)‐configuration bound preferentially to 5‐HT2A over 5‐HT2C receptors and had >100‐fold selectivity over 5‐HT2B and H1 receptors. Results suggest that G2385.42 and V2355.39 in 5‐HT2A receptors (conserved in 5‐HT2C receptors) are important for high affinity binding, whereas interactions with T1945.42 and W1584.56 determine H1 receptor affinity. The 4‐PAT analog (2S,4R)‐4‐(4'‐(dimethylamino)‐[1,1'‐biphenyl]‐3‐yl)‐N,N‐dimethyl‐1,2,3,4‐tetrahydronaphthalen‐2‐amine, (2S,4R)‐2k, a potent and selective 5‐HT2A/5‐HT2C receptor inverse agonist, had activity like pimavanserin in the mouse head twitch response assay but was distinct in not suppressing locomotor activity. Conclusions and Implications The novel 4‐PAT chemotype can yield selective 5‐HT2A/5‐HT2C receptor inverse agonists for antipsychotic drug development by optimizing ligand–receptor interactions in transmembrane domain 5. Chirality can be exploited to attain selectivity over H1 receptors, which may circumvent sedative effects.

Design, Synthesis, Molecular Docking, and Biological Evaluation of Novel Pimavanserin-Based Analogues as Potential Serotonin 5-HT2A Receptor Inverse Agonists

“…It is reported that these residues are essential chemical features of the 5-HT 2A receptor and made major contribution for antagonist activity. Interestingly, the ligands displayed C−H binding interactions with Val235 and vdW bonds with Gly238, and Ser242 in both 5-HT 2A structures (Figure 10−13) where the positions of these residues are close enough to the side-extended cavity 41 (Table 5). Obviously, compound 3 displayed the highest predicted binding affinity for both PDB sequences of the serotonin 5-HT 2A receptor: −9.7 and −9.8 kcal/mol.…”

“…In contrast, the docked poses of pimavanserin with different GPCRs showed poor fitting at the side cavities of these receptors and demonstrate shallow binding to accommodate the isobutoxybenzyl group of pimavanserin. In a different approach, Casey et al 41 studied the binding of pimavanserin to 5-HT 2A receptors. They performed molecular modeling experiments and site-directed mutagenesis for specific residues to validate the interaction sites of pimavanserin with the 5-HT 2A receptor.…”

“…The hollow of this pocket is surrounded by conserved hydrophobic residues on TM3, TM4, and TM5 and located near the orthosteric sites where specific ligands bind in the 5-HT 2A receptor . It was pointed out , that the location of several amphipathic and hydrophobic side chains (Val 235, Gly238, and Ser 242) in this region of the binding pocket was close enough to the isobutoxybenzyl of pimavanserin and that these ensembles of non-conserved residues contribute to the subtype-selective antagonist property (Figure ). The distinct chemical structure of pimavanserin permits the isobutoxybenzyl group to occupy a side-extended cavity in TM5 to a deeper region (to the far left of the pocket) (Figure ).…”

“…Unfortunately, this work did not describe the methods of synthesis and the information about chemistry of the significant intermediates was insufficient. In 2022, Casey and co-workers 41 explored the synthesis of different diastereomers of novel 2-dimethylaminotetralins that bound serotonin 5-HT 2 and histamine H 1 receptors, trying to improve selectivity of 5-HT 2A over 5-HT 2B and H 1 receptors.…”

Conformationally Selective 2-Aminotetralin Ligands Targeting the alpha2A- and alpha2C-Adrenergic Receptors

“…Docks were developed via a modified version of a procedure that has been used in our laboratory and previously described . Three-dimensional ligands were assembled in Maestro (Schrodinger, New York, NY) and optimized via an ab initio quantum chemistry method at the HF/6-31G* level, followed by single-point energy calculations of molecular electrostatic potential for charge fitting with Gaussian 16 .…”