Pharmacodynamics study of a new 5-HT2A receptor inverse agonist PCC03039
Authors:   School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shangdong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai 264005, China, Liu Sujie , Wang Xin ,   School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shangdong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai 264005, China, Gao Huan ,   School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shangdong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai 264005, China, Ye Liang ,   School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shangdong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai 264005, China, Tian Jingwei ,   [1] School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shangdong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai; [2] R & D Center, Luye Pharma Group Ltd., Yantai 264003, China 264005, China, Du Guangying ,   School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shangdong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai 264005, China
Published: March 2022

The purpose of this paper is to evaluate the pharmacodynamics of a new 5-HT2A receptor inverse agonist PCC03039 and provide data support for its druggability and clinical trial application. In the in vitro efficacy studies, the affinities of PCC03039 for 5-HT2A, 5-HT2B, and 5-HT2C receptors and the inverse agonistic and antagonistic activities of 5-HT2A receptors were detected; in the in vivo efficacy studies, the pharmacodynamic effects of PCC03039 on DOI-induced rat head-twitch model and MK-801-induced rat hyperlocomotion model were observed. The results of the studies showed that the affinities of PCC03039 for the 5-HT2 receptors were comparable to those of the marketed drug pimavanserin, however, the inverse agonistic and antagonistic activities of PCC03039 for the 5-HT2A receptor were significantly improved, with IC50 values of 2.11 nM and 1.33 nM, which were 20-fold and 21-fold higher than that of pimavanserin, respectively. PCC03039 could dose-dependently inhibit DOI-induced head-twitch and MK-801-induced hyperlocomotion in SD rats, and the pharmacodynamic effect was significantly better than pimavanserin at the equimolar dose. The above results show that PCC03039 has better pharmacodynamic activity in vitro and in vivo than pimavanserin, and has good druggability from the perspective of pharmacodynamics.