Discovery of Procognitive Antipsychotics by Combining Muscarinic M1 Receptor Structure-Activity Relationship with Systems Response Profiles in Zebrafish Larvae.,ACS Chemical Neuroscience

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Discovery of Procognitive Antipsychotics by Combining Muscarinic M1 Receptor Structure-Activity Relationship with Systems Response Profiles in Zebrafish Larvae.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-01-03 , DOI: 10.1021/acschemneuro.9b00524
Karin Hellman ₁ , Jörgen Ohlsson ₁ , Marcus Malo ₂ , Roger Olsson _{1,

2} , Fredrik Ek ₁

Affiliation

Current antipsychotic drugs are notably ineffective at addressing the cognitive deficits associated with schizophrenia. N-Desmethylclozapine (NDMC), the major metabolite of clozapine, displays muscarinic M1 receptor (M1) agonism, an activity associated with improvement in cognitive functioning. Preclinical and clinical data support that M1 agonism may be a desired activity in antipsychotic drugs. However, NDMC failed clinical phase II studies in acute psychotic patients. NDMC analogues were synthesized to establish a structure-activity relationship (SAR) at the M1 receptor as an indication of potential procognitive properties. In vitro evaluation revealed a narrow SAR in which M1 agonist activity was established by functionalization in the 4- and 8-positions in the tricyclic core. In vivo behavioral response profiles were used to evaluate antipsychotic efficacy and exposure in zebrafish larvae and peripheral side effect related M1 activity in adult zebrafish. The NDMC analogue 13f demonstrated antipsychotic activity similar to clozapine including M1 agonist activity. Cotreatment with trospium chloride, an M1 peripheral acting antagonist, counteracted peripheral side effects. Thus, the NDMC analogue 13f, in combination with a peripherally acting anticholinergic compound, could be suitable for further development as an antipsychotic compound with potential procognitive activity.

中文翻译：

通过将毒蕈碱型M1受体结构-活性关系与斑马鱼幼虫的系统反应谱相结合，发现预防性抗精神病药。

当前的抗精神病药在解决与精神分裂症有关的认知缺陷方面尤其无效。N-去甲基氯氮平（NDMC）是氯氮平的主要代谢产物，具有毒蕈碱M1受体（M1）激动作用，该活性与认知功能的改善有关。临床前和临床数据支持M1激动可能是抗精神病药物中所需的活性。但是，NDMC在急性精神病患者的临床II期研究中失败了。合成NDMC类似物以在M1受体上建立结构-活性关系（SAR），以表明潜在的认知特性。体外评估显示狭窄的SAR，其中通过在三环核心的4位和8位功能化来建立M1激动剂活性。体内行为反应概况用于评估成年斑马鱼在斑马鱼幼虫中的抗精神病功效和暴露以及与外周不良反应有关的M1活性。NDMC类似物13f具有类似于氯氮平的抗精神病活性，包括M1激动剂活性。与氯化钾（一种M1外围作用拮抗剂）共同治疗可抵消外围副作用。因此，NDMC类似物13f与外围作用的抗胆碱能化合物结合，可能适合作为具有潜在的认知活性的抗精神病化合物进一步开发。与氯化钾（一种M1外围作用拮抗剂）共同治疗可抵消外围副作用。因此，NDMC类似物13f与外围作用的抗胆碱能化合物结合，可能适合作为具有潜在的认知活性的抗精神病化合物进一步开发。与氯化钾（一种M1外围作用拮抗剂）共同治疗可抵消外围副作用。因此，NDMC类似物13f与外围作用的抗胆碱能化合物结合，可能适合作为具有潜在的认知活性的抗精神病化合物进一步开发。

更新日期：2020-01-04

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