Functionally Biased D2R Antagonists: Targeting the β-Arrestin Pathway to Improve Antipsychotic Treatment was written by Weiwer, Michel;Xu, Qihong;Gale, Jennifer P.;Lewis, Michael;Campbell, Arthur J.;Schroeder, Frederick A.;Van de Bittner, Genevieve C.;Walk, Michelle;Amaya, Aldo;Su, Ping;Dordevic, Luka;Sacher, Joshua R.;Skepner, Adam;Fei, David;Dennehy, Kelly;Nguyen, Shannon;Faloon, Patrick W.;Perez, Jose;Cottrell, Jeffrey R.;Liu, Fang;Palmer, Michelle;Pan, Jen Q.;Hooker, Jacob M.;Zhang, Yan-Ling;Scolnick, Edward;Wagner, Florence F.;Holson, Edward B.. And the article was included in ACS Chemical Biology in 2018.Formula: C11H21NO3 This article mentions the following:
Schizophrenia is a severe neuropsychiatric disease that lacks completely effective and safe therapies. As a polygenic disorder, genetic studies have only started to shed light on its complex etiol. To date, the pos. symptoms of schizophrenia are well-managed by antipsychotic drugs, which primarily target the dopamine D2 receptor (D2R). However, these antipsychotics are often accompanied by severe side effects, including motoric symptoms. At D2R, antipsychotic drugs antagonize both G-protein dependent (Gαi/o) signaling and G-protein independent (β-arrestin) signaling. However, the relevant contributions of the distinct D2R signaling pathways to antipsychotic efficacy and on-target side effects (motoric) are still incompletely understood. Recent evidence from mouse genetic and pharmacol. studies point to β-arrestin signaling as the major driver of antipsychotic efficacy and suggest that a β-arrestin biased D2R antagonist could achieve an addnl. level of selectivity at D2R, increasing the therapeutic index of next generation antipsychotics. Here, we characterize BRD5814, a highly brain penetrant β-arrestin biased D2R antagonist. BRD5814 demonstrated good target engagement via PET imaging, achieving efficacy in an amphetamine-induced hyperlocomotion mouse model with strongly reduced motoric side effects in a rotarod performance test. This proof of concept study opens the possibility for the development of a new generation of pathway selective antipsychotics at D2R with reduced side effect profiles for the treatment of schizophrenia. In the experiment, the researchers used many compounds, for example, 1-Boc-4-Hydroxy-4-methylpiperidine (cas: 406235-30-1Formula: C11H21NO3).
1-Boc-4-Hydroxy-4-methylpiperidine (cas: 406235-30-1) belongs to piperidine derivatives. Piperidine is a metabolite of cadaverine, a polyamine found in the human intestine. Piperidine prefers a chair conformation, similar to cyclohexane. Unlike cyclohexane, piperidine has two distinguishable chair conformations: one with the N–H bond in an axial position, and the other in an equatorial position.Formula: C11H21NO3
Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem