Antidepressant-like and anxiolytic-like effects of YL-IPA08, a potent ligand for the translocator protein (18 kDa).
It has been demonstrated that the translocator protein (18 kDa) (TSPO) plays an important role in stress-response and stress-related disorders, such as anxiety and depression, by affecting the production of neurosteroids, supporting the potential use of selective TSPO ligands as antidepressant or anxiolytic drugs. N-ethyl-N-(2-pyridinylmethyl)- 2-(3,4-ichlorophenyl)- 7-methylimidazo [1,2-a] pyridine-3-acetamide hydrochloride (YL-IPA08), a novel TSPO ligand that has been synthesized at our institute, exerted a high affinity for TSPO in a crude mitochondrial fraction prepared from rat cerebellum but exhibited only a negligible affinity for the central benzodiazepine receptor. As expected, YL-IPA08 incubation with the cultured rat astrocyte cells increased the pregnenolone and progesterone concentration from the cultured medium. Moreover, YL-IPA08 produced significant antidepressant-like and anxiolytic-like effects in a series of mouse and rat behavior models. In addition, the antidepressant-like behavior of YL-IPA08 was totally blocked by the TSPO antagonist PK11195 in a tail suspension test, and the anxiolytic effect was blocked by PK11195 but not by a CBR antagonist in the elevated plus-maze test. Furthermore, compared with the CBR agonist diazepam, YL-IPA08 had no myorelaxant effects and did not affect the motor coordination, memory or hexobarbitone-induced sleep in mice. Overall, these results indicate that YL-IPA08 is a more potent and selective TSPO ligand, which exerts antidepressant-like and anxiolytic-like effects on behaviors that are mediated by TSPO but does not cause the side effects that are typically associated with conventional benzodiazepines.
Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing, PR China.
Li-Ming
LM
Zhang
Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing, PR China.
Nan
N
Zhao
Department of Anesthesiology, General Hospital of Beijing Military Command, Beijing 100007, China.
Wen-Zhi
WZ
Guo
Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing, PR China.
Zeng-Liang
ZL
Jin
Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing, PR China; Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, 1023 Shatainan Road, Guangzhou, PR China.
Zhi-Kun
ZK
Qiu
Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing, PR China.
Hong-Xia
HX
Chen
Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing, PR China.
Rui
R
Xue
Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing, PR China.
You-Zhi
YZ
Zhang
Department of Medicinal Chemistry, Beijing Institute of Pharmacology and Toxicology, Beijing, PR China.
Ri-Fang
RF
Yang
Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing, PR China. Electronic address: lyf619@aliyun.com.
Yun-Feng
YF
Li
D000818:Animals; D014151:Anti-Anxiety Agents / Q000627:therapeutic use*; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001007:Anxiety / Q000188:drug therapy* / Q000523:psychology; D002599:Chalcone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D003213:Conditioning, Psychological / Q000187:drug effects; D003863:Depression / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013550:Swimming / Q000523:psychology
C538718:1-(2-methoxy-4,6-bis(methoxymethoxy)phenyl)-3-(3-nitrophenyl)prop-2-en-1-one; D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D002599:Chalcone
Antidepressant; Anxiolytic; Neurosteroids; The translocator protein 18KD; YL-IPA08