The influence of substitution at aromatic part of 1,2,3,4-tetrahydroisoquinoline on in vitro and in vivo 5-HT1A/5-HT2A receptor activities of its 1-adamantoyloaminoalkyl derivatives Original Research Article

Further structure–activity relationship (SAR) studies with the 1,2,3,4-tetrahydroisoquinoline (THIQ) class of 5-HT1A ligands led to the synthesis of new 1-adamantoyloaminoalkyl derivatives. The impact of substituent variations in the aromatic part of THIQ moiety on 5-HT1A and 5-HT2A receptor affinities, as well as in vivo functional properties of the investigated compounds were discussed. It was found that those modifications reduced the binding affinity for 5-HT1A receptors (in comparison with unsubstituted THIQ derivatives); however, the majority of new compounds still remained potent 5-HT1A ligands (Ki=4.9–46 nM) and most of them showed features of partial agonists of postsynaptic 5-HT1A receptors. At the same time, their 5-HT2A receptor affinity was slightly increased (Ki=40–1475 nM), which resulted in a loss of 5-HT2A/5-HT1A selectivity. 5-Br,8-OCH3 derivative—the most potent, mixed 5-HT1A/5-HT2A ligand—produced activation of presynaptic 5-HT1A receptors and showed properties of a 5-HT2A receptor antagonist.