Design, Synthesis and 5-HT_1A Binding Affinity of <i>N</i>-(3-(4-(2-Methoxyphenyl)piperazin-1-yl)propyl)tricyclo[3.3.1.1^3,7]decan-1-amine and <i>N</i>-(3-(4-(2-Methoxyphenyl)piperazin-1-yl)propyl)-3,5-dimethyl-tricylo[3.3.1.1^3,7]decan-1-amine

Abstract

Based on previously highlighted structural features, the development of highly selective 5-HT1A receptor inhibitors is closely linked to the incorporation of a 4-alkyl-1-arylpiperazine scaffold on them. In this paper, we present the synthesis of two new compounds bearing the 2-MeO-Ph-piperazine moiety linked via a three carbon atom linker to the amine group of 1-adamantanamine and memantine, respectively. Both were tested for their binding affinity against 5-HT1A receptor. N-(3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)tricyclo[3.3.1.13,7]decan-1-amine fumarate (8) and N-(3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-3,5-dimethyl-tricylo[3.3.1.13,7]decan-1-amine fumarate (10) proved to be highly selective ligands towards 5-HT1A receptor with a binding constant of 1.2 nM and 21.3 nM, respectively, while 5-carboxamidotriptamine (5-CT) (2) was used as an internal standard for this assay with a measured Ki = 0.5 nM.

Keywords

• serotonin receptors
• 5-HT_1A receptors
• arylpiperazine inhibitors
• carbocyclic rings
• cage-like structures
• blood-brain barrier