Journal of Medicinal Chemistry p. 10946 - 10971 (2020)
Update date:2022-08-15
Topics:
Sniecikowska, Joanna
Gluch-Lutwin, Monika
Bucki, Adam
Wi?ckowska, Anna
Siwek, Agata
Jastrzebska-Wiesek, Magdalena
Partyka, Anna
Wilczyńska, Daria
Pytka, Karolina
Latacz, Gniewomir
Przejczowska-Pomierny, Katarzyna
Wyska, El?bieta
Weso?owska, Anna
Paw?owski, Maciej
Newman-Tancredi, Adrian
Kolaczkowski, Marcin
Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives with high affinity and selectivity for serotonin 5-HT1A receptors were obtained and tested in four functional assays: ERK1/2 phosphorylation, adenylyl cyclase inhibition, calcium mobilization, and β-arrestin recruitment. Compounds 44 and 56 (2-methylaminophenoxyethyl and 2-(1H-indol-4-yloxy)ethyl derivatives, respectively) were selected as biased agonists with highly differential "signaling fingerprints"that translated into distinct in vivo profiles. In vitro, 44 showed biased agonism for ERK1/2 phosphorylation and, in vivo, it preferentially exerted an antidepressant-like effect in the Porsolt forced swimming test in rats. In contrast, compound 56 exhibited a first-in-class profile: it preferentially and potently activated β-arrestin recruitment in vitro and potently elicited lower lip retraction in vivo, a component of "serotonergic syndrome". Both compounds showed promising developability properties. The presented 5-HT1A receptor-biased agonists, preferentially targeting various signaling pathways, have the potential to become drug candidates for distinct central nervous system pathologies and possessing accentuated therapeutic activity and reduced side effects.
View MoreBeijing Apis Biotechnology Co., Ltd.
Contact:86-010-67856775-8551
Address:NO.4PUHUANGYU ROAD,FENTAI DISTRICT, BEIJING, CHINA
Contact:+86 21 5017 5386
Address:No 999,Jiangyue Rd, Minhang Dist ,201114,Shanghai ,China
Chemsigma International Co.,Ltd.
website:http://www.chemsigma.com
Contact:86-025-58748998
Address:Rm.705, 15th Building,Rd.Xinke II
Contact:+86-025-52406782
Address:8 Taizishan Rd., Yanjiang Industrial Development Area, Nanjing, Jiangsu, China.
HENAN NEW BLUE CHEMICAL CO.,LTD
website:http://www.newbluechem.com
Contact:86-371-55170693/55170694
Address:Zhengzhou International Trade New Territory,Jinshui District,Zhengzhou ,China
Doi:10.1021/cc1001617
(2010)Doi:10.1016/j.tet.2012.05.103
(2012)Doi:10.1248/cpb.31.366
(1983)Doi:10.1055/s-0031-1279995
(2011)Doi:10.1002/ejoc.201403465
(2015)Doi:10.1016/j.inoche.2012.04.002
(2012)