TY - JOUR
T1 - The Novel Pimavanserin Derivative ST-2300 with Histamine H3 Receptor Affinity Shows Reduced 5-HT2A Binding, but Maintains Antidepressant-and Anxiolytic-like Properties in Mice
AU - Venkatachalam, Karthikkumar
AU - Zhong, Sicheng
AU - Dubiel, Mariam
AU - Satała, Grzegorz
AU - Sadek, Bassem
AU - Stark, Holger
N1 - Funding Information:
The authors acknowledge the partial support of DFG INST 208/664-1 FUGG and COST Actions CA15135, CA18133, and CA18240, which were kindly provided to HS. MD and HS participate in the DFG funded GRK2158 “Natural products and natural product analogs against therapy-resistant tumors and microorganism”. The Office of Graduate Studies and Research of UAE University as well as Zayed-Center for Health Sciences are thanked for the support provided to BS with funds (31R233 and 12M099).
Funding Information:
Funding: The authors acknowledge the partial support of DFG INST 208/664-1 FUGG and COST Actions CA15135, CA18133, and CA18240, which were kindly provided to HS. MD and HS participate in the DFG funded GRK2158 “Natural products and natural product analogs against therapy-resistant tumors and microorganism”. The Office of Graduate Studies and Research of UAE University as well as Zayed-Center for Health Sciences are thanked for the support provided to BS with funds (31R233 and 12M099).
Publisher Copyright:
© 2022 by the author. Licensee MDPI, Basel, Switzerland.
PY - 2022/5
Y1 - 2022/5
N2 - The therapy of depression is challenging and still unsatisfactory despite the presence of many antidepressant drugs on the market. Consequently, there is a continuous need to search for new, safer, and more effective antidepressant therapeutics. Previous studies have suggested a potential association of brain histaminergic/serotoninergic signaling and antidepressant-and anxio-lytic-like effects. Here, we evaluated the in vivo antidepressant-and anxiolytic-like effects of the newly developed multiple-active ligand ST-2300. ST-2300 was developed from 5-HT2A/2C inverse agonist pimavanserin (PIM, ACP-103) and incorporates a histamine H3 receptor (H3R) antagonist pharmacophore. Despite its parent compound, ST-2300 showed only moderate serotonin 5-HT2A antagonist/inverse agonist affinity (Ki value of 1302 nM), but excellent H3R affinity (Ki value of 14 nM). In vivo effects were examined using forced swim test (FST), tail suspension test (TST), and the open field test (OFT) in C57BL/6 mice. Unlike PIM, ST-2300 significantly increased the anxiolytic-like effects in OFT without altering general motor activity. In FST and TST, ST-2300 was able to reduce immobility time similar to fluoxetine (FLX), a recognized antidepressant drug. Importantly, pretreatment with the CNS-penetrant H3R agonist (R)-α-methylhistamine reversed the antidepres-sant-like effects of ST-2300 in FST and TST, but failed to reverse the ST-2300-provided anxiolytic effects in OFT. Present findings reveal critical structural features that are useful in a rational multi-ple-pharmacological approach to target H3R/5-HT2A/5-HT2C.
AB - The therapy of depression is challenging and still unsatisfactory despite the presence of many antidepressant drugs on the market. Consequently, there is a continuous need to search for new, safer, and more effective antidepressant therapeutics. Previous studies have suggested a potential association of brain histaminergic/serotoninergic signaling and antidepressant-and anxio-lytic-like effects. Here, we evaluated the in vivo antidepressant-and anxiolytic-like effects of the newly developed multiple-active ligand ST-2300. ST-2300 was developed from 5-HT2A/2C inverse agonist pimavanserin (PIM, ACP-103) and incorporates a histamine H3 receptor (H3R) antagonist pharmacophore. Despite its parent compound, ST-2300 showed only moderate serotonin 5-HT2A antagonist/inverse agonist affinity (Ki value of 1302 nM), but excellent H3R affinity (Ki value of 14 nM). In vivo effects were examined using forced swim test (FST), tail suspension test (TST), and the open field test (OFT) in C57BL/6 mice. Unlike PIM, ST-2300 significantly increased the anxiolytic-like effects in OFT without altering general motor activity. In FST and TST, ST-2300 was able to reduce immobility time similar to fluoxetine (FLX), a recognized antidepressant drug. Importantly, pretreatment with the CNS-penetrant H3R agonist (R)-α-methylhistamine reversed the antidepres-sant-like effects of ST-2300 in FST and TST, but failed to reverse the ST-2300-provided anxiolytic effects in OFT. Present findings reveal critical structural features that are useful in a rational multi-ple-pharmacological approach to target H3R/5-HT2A/5-HT2C.
KW - 5-HT2A receptor
KW - ACP-103
KW - antidepres-sant
KW - anxiolytic
KW - fluoxetine
KW - forced swim test
KW - histamine H3 receptor
KW - open field test
KW - pimavanserin
KW - tail suspension test
UR - http://www.scopus.com/inward/record.url?scp=85129714356&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85129714356&partnerID=8YFLogxK
U2 - 10.3390/biom12050683
DO - 10.3390/biom12050683
M3 - Article
C2 - 35625611
AN - SCOPUS:85129714356
SN - 2218-273X
VL - 12
JO - Biomolecules
JF - Biomolecules
IS - 5
M1 - 683
ER -