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

Bioorg Med Chem Lett. 2020 Aug 15;30(16):127358. doi: 10.1016/j.bmcl.2020.127358.

Colleen A Evans ¹, Andrea Zuluaga ², Diego Vasquez Matute ², Sarah Baradaran-Noviri ², Natalia Perez-Cervantes ², Maxime A Siegler ³

Affiliations

1 Science Department, Dominican College, 470 Western Highway, Orangeburg, NY 10962, USA. Electronic address: Colleen.Evans@dc.edu.
2 Science Department, Dominican College, 470 Western Highway, Orangeburg, NY 10962, USA.
3 Department of Chemistry, Small Molecule X-ray Crystallography Facility, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218, USA.

PMID: 32631554 DOI: 10.1016/j.bmcl.2020.127358

Abstract

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-HTR_1A (EC₅₀ 6.7 nM) and antagonist activity against 5-HTR_2A (IC₅₀ 62.3 nM) and was selective over 5-HTR_2C receptor (IC₅₀ > 3333 nM) in the PathHunter® β-arrestin assays.

Keywords

5-HTR(1A) partial agonist; 5-HTR(2A) antagonist; Adatanserin; Tandem alkylation; Thioadatanserin; Thionation; β-arrestin.

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