Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 22, Pages 10017-10039Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b01096
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Funding
- China Postdoctoral Science Foundation [2017M612473]
- NSFC [81573291]
- National Science and Technology Major Project Key New Drug Creation and Manufacturing Program [2018ZX09711002-013-004]
- National Major Scientific and Technological Special Project for Significant New Drugs Development [2018ZX9711002-013-004, 2018ZX09735001-003]
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Herein, a novel series of multireceptor ligands was developed as polypharmacological antipsychotic agents using the designed multiple ligand approach between dopamine receptors and serotonin receptors. Among them, compound 47 possessed unique pharmacological features, exhibiting high affinities for D-2, D-3, 5-HT1A, 5-HT2A, and 5-HT6 receptors and low efficacy at the off-target receptors (5-HT2C, histamine H-1, and adrenergic alpha(1) receptor). Compound 47 showed dose-dependent inhibition of apomorphine- and MK-801-induced motor behavior, and the conditioned avoidance response with low cataleptic effect. Moreover, compound 47 resulted nonsignificantly serum prolactin levels and weight gain change compared with risperidone. Additionally, compound 47 possessed a favorable pharmacokinetic profile with oral bioavailability of 58.8% in rats. Furthermore, compound 47 displayed procognition properties in a novel object recognition task in rats. Taken together, compound 47 may constitute a novel class of atypical antipsychotic drugs for schizophrenia.
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