A new class of 5-HT2A /5-HT2C 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-HT_2A and 5-HT_2C are important neurotherapeutic targets, though, obtaining selectivity over 5-HT_2B and H₁ receptors is challenging. Here, we delineated molecular determinants of selective binding to 5-HT_2A and 5-HT_2C 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-HT_2A receptor mutagenesis studies were performed to understand structure-activity relationships at 5-HT₂ -type and H₁ receptors. Lead 4-PAT-type 5-HT_2A /5-HT_2C receptor inverse agonists were compared with pimavanserin, a selective 5-HT_2A /5-HT_2C 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-HT_2A , 5-HT_2C and H₁ receptors, with >100-fold selectivity over 5-HT_2B receptors, whereas diastereomers in the (2R,4R)-configuration bound preferentially to 5-HT_2A over 5-HT_2C receptors and had >100-fold selectivity over 5-HT_2B and H₁ receptors. Results suggest that G238^5.42 and V235^5.39 in 5-HT_2A receptors (conserved in 5-HT_2C receptors) are important for high affinity binding, whereas interactions with T194^5.42 and W158^4.56 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-HT_2A /5-HT_2C 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-HT_2A /5-HT_2C 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.

Keywords: 5-HT2A; 5-HT2B; 5-HT2C; GPCR; H1; pimavanserin; polypharmacology.