Discovery of a new class of multi-target heterocycle piperidine derivatives as potential antipsychotics with pro-cognitive effect. (15th May 2021)

• Record Type: Journal Article
• Authors: Gao, Lanchang; Hao, Chao; Chen, Jiali; Ma, Ru; Zheng, Lu; Wu, Qingkun; Liu, Xin; Liu, Bi-Feng; Zhang, Guisen; Chen, Yin; Jin, Jian
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 40(2021)
• Publication Date: 2021-05-15
• Subjects: Dopamine -- Serotonin -- Multi-target -- Atypical antipsychotics -- Cognition; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2021.127909
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: In vitro ( K i, nM): D2, 10.5; D3, 9.6; 5-HT1A, 5.6; 5-HT2A, 8.4; H3, 14.0; 5-HT6, 141.0; H1, 968.3; 5-HT2C, 610.4; α1, 438.2. In vivo (ED50, mg/Kg): APO, 0.09; MK-801, 0.2; CAT, 32.0; CAR, 1.3. Pharmacokinetic: t1/2, 5.0 h; F%, 24.0. Highlights: A series novel benzoisoxazoleylpiperidine derivative was designed and synthesized. Compound 4w shown showed highest affinities to D2, 5-HT1A, 5-HT2A and H3 receptors. Compound 4w has alleviated the schizophrenia-like symptoms and reduced side effects. Compound 4w showed favorable pharmacokinetic profile. Abstract: A series of benzoisoxazoleylpiperidine derivatives were synthesized by using the multi-target strategies and their potent affinities for dopamine (DA), serotonin (5-HT) and human histamine H3 receptors have been evaluated. Of these compounds, the promising candidate 4w displayed high affinities for D2, D3, 5-HT1A, 5-HT2A and H3, a moderate affinity for 5-HT6, negligible effects on the human ether-a-go-go-related gene (hERG) channel, low affinities for off-target receptors (5-HT2C, adrenergic α1 and H1 ). In addition, the animal behavioral study revealed that, compared to risperidone, compound 4w significantly inhibited apomorphine-induced climbing and MK-801-induced movement behaviors with a high threshold for catalepsy and low liabilities for weight gain and hyperprolactinemia. Results from the conditioned avoidance response test and novel object recognition task demonstrated that 4w had pro-cognitive effects. Thus, the antipsychotic drug-like activities of 4w indicate that it may be a potential polypharmacological antipsychotic candidate drug.