Casey Austen B, Mukherjee Munmun, McGlynn Ryan P, Cui Meng, Kohut Stephen J, Booth Raymond G
Center for Drug Discovery, Northeastern University, Boston, Massachusetts, USA.
Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts, USA.
Br J Pharmacol. 2022 Jun;179(11):2610-2630. doi: 10.1111/bph.15756. Epub 2022 Mar 7.
The 5-HT receptor subtypes 5-HT and 5-HT are important neurotherapeutic targets, though, obtaining selectivity over 5-HT and H receptors is challenging. Here, we delineated molecular determinants of selective binding to 5-HT and 5-HT receptors for novel 4-phenyl-2-dimethylaminotetralins (4-PATs).
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 receptor mutagenesis studies were performed to understand structure-activity relationships at 5-HT -type and H receptors. Lead 4-PAT-type 5-HT /5-HT receptor inverse agonists were compared with pimavanserin, a selective 5-HT /5-HT 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.
Most 4-PAT diastereomers in the (2S,4R)-configuration bound non-selectively to 5-HT , 5-HT and H receptors, with >100-fold selectivity over 5-HT receptors, whereas diastereomers in the (2R,4R)-configuration bound preferentially to 5-HT over 5-HT receptors and had >100-fold selectivity over 5-HT and H receptors. Results suggest that G238 and V235 in 5-HT receptors (conserved in 5-HT receptors) are important for high affinity binding, whereas interactions with T194 and W158 determine H 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 /5-HT receptor inverse agonist, had activity like pimavanserin in the mouse head twitch response assay but was distinct in not suppressing locomotor activity.
The novel 4-PAT chemotype can yield selective 5-HT /5-HT receptor inverse agonists for antipsychotic drug development by optimizing ligand-receptor interactions in transmembrane domain 5. Chirality can be exploited to attain selectivity over H receptors, which may circumvent sedative effects.
5-羟色胺（5-HT）受体亚型5-HT和5-HT是重要的神经治疗靶点，然而，要获得对5-HT和H受体的选择性颇具挑战。在此，我们阐述了新型4-苯基-2-二甲基氨基四氢萘（4-PATs）与5-HT和5-HT受体选择性结合的分子决定因素。
我们合成了42种在C(4)-苯基间位带有卤素或芳基部分的新型4-PATs。进行了亲和力、功能、分子建模和5-HT受体诱变研究，以了解5-HT型和H受体的构效关系。在小鼠头部抽搐反应和运动活性测定中，将先导4-PAT型5-HT /5-HT受体反向激动剂与已获批用于治疗帕金森病相关精神病的选择性5-HT /5-HT受体反向激动剂匹莫范色林进行比较，这些模型与抗精神病药物研发相关。
大多数（2S,4R）构型的4-PAT非对映异构体与5-HT、5-HT和H受体非选择性结合，对5-HT受体的选择性大于100倍，而（2R,4R）构型的非对映异构体优先与5-HT而非5-HT受体结合，对5-HT和H受体的选择性大于100倍。结果表明，5-HT受体（在5-HT受体中保守）中的G238和V235对高亲和力结合很重要，而与T194和W158的相互作用决定H受体亲和力。4-PAT类似物（2S,4R）-4-（4'-（二甲基氨基）-[1,1'-联苯]-3-基）-N,N-二甲基-1,2,3,4-四氢萘-2-胺，即（2S,4R）-2k，是一种强效且选择性的5-HT /5-HT受体反向激动剂，在小鼠头部抽搐反应测定中的活性与匹莫范色林相似，但在不抑制运动活性方面有所不同。
新型4-PAT化学型可通过优化跨膜结构域5中的配体-受体相互作用，产生用于抗精神病药物研发的选择性5-HT /5-HT受体反向激动剂。可利用手性来获得对H受体的选择性，这可能规避镇静作用。
