Design, Synthesis, and Biological Evaluation of Phenol Bioisosteric Analogues of 3-Hydroxymorphinan

• Published in: Scientific reports 2019-02, Vol.9 (1), p.2247-2247, Article 2247
• Main Authors: Li, Ziqiang, Bao, Xiuqi, Bai, Xiaoguang, Zhang, Guoning, Wang, Juxian, Zhu, Mei, Wang, Yue, Shang, Junmei, Sheng, Chanjuan, Zhang, Dan, Wang, Yucheng
• Format: Article
• Language: English
• Subjects: 101/58; 140/131; 631/154; 631/92; 64/60; Animal research; Bioavailability; Dopamine; Humanities and Social Sciences; Inflammation; Lipopolysaccharides; Metabolism; Metabolites; Microglia; Movement disorders; MPTP; multidisciplinary; Neurodegenerative diseases; Neurons; Neuroprotection; Neurotoxicity; Parkinson's disease; Pharmacokinetics; Phenolic compounds; Phenols; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-38911-1

The neuroprotective agent 3-hydroxymorphinan (3-HM) is a well-documented and highly safe therapeutic intervention for the inflammatory-related effects of Parkinson’s disease (PD). However, the bioavailability of 3-HM is very low due to the rapid first-pass metabolism of the phenolic moiety. In the present study, we sought to improve the metabolic stability and overall pharmacokinetic profile of 3-HM. Based on an iterative design process that a suitably arranged heterocycle with an NH group would serve as the metabolically stable isostere of the phenolic group, we designed and synthesized two analogues of 3-HM. Benzimidazolone compound 8 (imidazolone-morphinan) was comparable in activity to 3-HM against lipopolysaccharide (LPS)-induced inflammatory responses in microglial BV2 cells and in vivo animal experiments (MPTP-induced PD mouse model). Moreover, the in vitro study showed that imidazolone-morphinan was non-toxic to microglia, indicating its high safety. Considering the favourable and unique preclinical profiles, compound 8 was nominated as a candidate for further clinical development.