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‐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…
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