Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT1A Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile.,Journal of Medicinal Chemistry

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Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT1A Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-09-04 , DOI: 10.1021/acs.jmedchem.0c00814
Joanna Sniecikowska ₁ , Monika Gluch-Lutwin ₁ , Adam Bucki ₁ , Anna Więckowska ₁ , Agata Siwek ₁ , Magdalena Jastrzebska-Wiesek ₁ , Anna Partyka ₁ , Daria Wilczyńska ₁ , Karolina Pytka ₁ , Gniewomir Latacz ₁ , Katarzyna Przejczowska-Pomierny ₁ , Elżbieta Wyska ₁ , Anna Wesołowska ₁ , Maciej Pawłowski ₁ , Adrian Newman-Tancredi ₂ , Marcin Kolaczkowski ₁

Affiliation

Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives with high affinity and selectivity for serotonin 5-HT_1A receptors were obtained and tested in four functional assays: ERK1/2 phosphorylation, adenylyl cyclase inhibition, calcium mobilization, and β-arrestin recruitment. Compounds 44 and 56 (2-methylaminophenoxyethyl and 2-(1H-indol-4-yloxy)ethyl derivatives, respectively) were selected as biased agonists with highly differential “signaling fingerprints” that translated into distinct in vivo profiles. In vitro, 44 showed biased agonism for ERK1/2 phosphorylation and, in vivo, it preferentially exerted an antidepressant-like effect in the Porsolt forced swimming test in rats. In contrast, compound 56 exhibited a first-in-class profile: it preferentially and potently activated β-arrestin recruitment in vitro and potently elicited lower lip retraction in vivo, a component of “serotonergic syndrome”. Both compounds showed promising developability properties. The presented 5-HT_1A receptor-biased agonists, preferentially targeting various signaling pathways, have the potential to become drug candidates for distinct central nervous system pathologies and possessing accentuated therapeutic activity and reduced side effects.

中文翻译：

发现新型pERK1 / 2或β-arrestin偏爱的5-HT1A受体偏向激动剂：多种治疗样与副作用的关系。

获得了对5-羟色胺5-HT _1A受体具有高亲和力和选择性的新型1-（1-苯甲酰基哌啶丁-4-基）甲胺衍生物，并在四种功能测定中进行了测试：ERK1 / 2磷酸化，腺苷酸环化酶抑制，钙动员和β-抑制蛋白的募集。选择化合物44和56（分别为2-甲基氨基苯氧基乙基和2-（1 H-吲哚-4-基氧基）乙基衍生物）作为具有高度差异性的“信号指纹”的偏向激动剂，这些信号被翻译成不同的体内特征。在体外，44显示出对ERK1 / 2磷酸化的偏向激动作用，而在体内，它在大鼠Porsolt强迫游泳试验中优先发挥了抗抑郁样作用。相反，化合物56表现出一流的特性：它在体外优先有效地激活β-arrestin募集，并在体内有效引起下唇缩回，这是“ 5-羟色胺能综合症”的一个组成部分。两种化合物均显示出良好的可显影性。提出的5-HT _1A受体偏向激动剂，优先针对各种信号传导途径，有可能成为独特的中枢神经系统病理学的候选药物，并具有增强的治疗活性和减少的副作用。

更新日期：2020-10-08

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