Design, Synthesis and Biological Investigation of Flavone Derivatives as Potential Multi-Receptor Atypical Antipsychotics
Open Access
- 8 September 2020
- Vol. 25 (18), 4107
- https://doi.org/10.3390/molecules25184107
Abstract
The design of a series of novel flavone derivatives was synthesized as potential broad-spectrum antipsychotics by using multi-receptor affinity strategy between dopamine receptors and serotonin receptors. Among them, 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl) piperidin- 1-yl) butoxy)-2,2-dimethylchroman-4-one (6j) exhibited a promising preclinical profile. Compound 6j not only showed high affinity for dopamine D2, D3, and serotonin 5-HT1A, 5-HT2A receptors, but was also endowed with low to moderate activities on 5-HT2C, α1, and H1 receptors, indicating a low liability to induce side effects such as weight gain, orthostatic hypotension and QT prolongation. In vivo behavioral studies suggested that 6j has favorable effects in alleviating the schizophrenia-like symptoms without causing catalepsy. Taken together, compound 6j has the potential to be further developed as a novel atypical antipsychotic.Funding Information
- Six Talent Peak Project in Jiangsu Province (2019-SWYY-128)
This publication has 32 references indexed in Scilit:
- Initial orthostatic hypotension and cerebral blood flow regulation: effect of α1-adrenoreceptor activityAmerican Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2013
- Human Ether-a-Go-Go-Related Gene Channel Blockers and its Structural Analysis for Drug DesignCurrent Drug Targets, 2013
- Reduced expression of haloperidol conditioned catalepsy in rats by the dopamine D3 receptor antagonists nafadotride and NGB 2904European Neuropsychopharmacology, 2012
- Animal models of schizophreniaBritish Journal of Pharmacology, 2011
- Metabolic side effects of antipsychotic drug treatment – pharmacological mechanismsPharmacology & Therapeutics, 2010
- Schizophrenia, “just the facts” 4. Clinical features and conceptualizationSchizophrenia Research, 2009
- Current schizophrenia drugs: efficacy and side effectsExpert Opinion on Pharmacotherapy, 2006
- α-Adrenoceptor modulation hypothesis of antipsychotic atypicalityProgress in Neuro-Psychopharmacology and Biological Psychiatry, 2003
- Catalepsy as a rodent model for detecting antipsychotic drugs with extrapyramidal side effect liabilityPsychopharmacology, 1995
- Dopamine D-2 antagonists reverse apomorphine-induced decreased water intake in the rat: prediction of antipsychotic drugs with few extrapyramidal side-effects?Journal of Neural Transmission, 1989