Synthesis and biological evaluation of thioadatanserin and its dialkylated products as partial 5-HTR1A agonists and 5-HTR2A antagonists for potential use in depression and anxiety disorders

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Thionation of adatanserin hydrochloride (2) with Lawesson's reagent in toluene/triethylamine afforded novel compound, (3r,5r,7r)-N-(2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)adamantane-1-carbothioamide (thioadatanserin, 3) in 84-90% isolated yield. Thioadatanserin underwent a tandem double alkylation with methyl iodide and benzyl bromide in NaH/THF to produce novel dialkylated products 6 and 7 respectively. The single X-ray crystal structure of 7 was determined to be 1-(2-((E- ((3r,5r,7r)-adamantan-1-yl)benzylthio)methylene)amino)ethyl)-1-benzyl-4- (pyrimidin-2-yl)piperazin-1-ium bromide showing that the piperazine ring adopts a chair-like configuration that is not co-planar with the pyrimidine ring. Thioadatanserin emerged as a dual potent partial agonist with activity against 5-HTR1A (EC50 6.7 nM) and antagonist activity against 5-HTR2A (IC50 62.3 nM) and was selective over 5-HTR2C receptor (IC50 > 3333 nM) in the PathHunter® β-arrestin assays.

Medienart:

E-Artikel

Erscheinungsjahr:

2020

Erschienen:

2020

Enthalten in:

Zur Gesamtaufnahme - volume:30

Enthalten in:

Bioorganic & medicinal chemistry letters - 30(2020), 16 vom: 15. Aug., Seite 127358

Sprache:

Englisch

Beteiligte Personen:

Evans, Colleen A [VerfasserIn]
Zuluaga, Andrea [VerfasserIn]
Vasquez Matute, Diego [VerfasserIn]
Baradaran-Noviri, Sarah [VerfasserIn]
Perez-Cervantes, Natalia [VerfasserIn]
Siegler, Maxime A [VerfasserIn]

Links:

Volltext

Themen:

β-arrestin
112692-38-3
5-HTR(1A) partial agonist
5-HTR(2A) antagonist
Adatanserin
Journal Article
Receptor, Serotonin, 5-HT1A
Receptor, Serotonin, 5-HT2A
Serotonin 5-HT1 Receptor Agonists
Serotonin 5-HT2 Receptor Antagonists
Tandem alkylation
Thioadatanserin
Thionation

Anmerkungen:

Date Completed 01.06.2021

Date Revised 01.06.2021

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1016/j.bmcl.2020.127358

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM312092237