Synthesis and biological investigation of new equatorial (β) stereoisomers of 3-aminotropane arylamides with atypical antipsychotic profile.

Abstract A series of novel 3β-aminotropane derivatives containing a 2-naphthalene or a 2-quinoline moiety was synthesised and evaluated for their affinity for 5-HT 1A , 5-HT 2A and D 2 receptors. Their affinity for the receptors was in the nanomolar to micromolar range. p -Substitution ( 6c , 6f , 6i , 6l , 6o ), as well as substitution with chlorine atoms ( 6g , 6h , 6i ), led to a significant increase in binding affinity for D 2 receptors with compounds 6f ( K i  = 0.6 nM), 6c and 6i ( K i  = 0.4 nM), having the highest binding affinities. m -Substituted derivatives were the most promising ligands in terms of 5-HT 2A receptor binding affinity whereas 2-quinoline derivatives ( 10a , 10b ) displayed the highest affinity for 5-HT 1A R and were the most selective ligands with K i  = 62.7 nM and K i  = 30.5 nM, respectively. Finally, the selected ligands 6b , 6d , 6e , 6g , 6h , 6k , 6n and 6o , with triple binding activity for the D 2 , 5-HT 1A and 5-HT 2A receptors, were subjected to in vivo tests, such as those for induced hypothermia, climbing behaviour and the head twitch response, in order to determine their pharmacological profile. The tested ligands presented neither agonist nor antagonist properties for the 5-HT 1A receptors in the induced hypothermia and lower lip retraction (LLR) tests. All tested compounds displayed antagonistic activity against 5-HT 2A , with 6n and 6o being the most active. Four ( 6b , 6k , 6n and 6o ) out of eight tested compounds could be classified as D 2 antagonists. Additionally, evaluation of metabolic stability was performed for selected ligands, and introduction of halogen atoms into the benzene ring of 6h , 6k , 6n and 6o improved their metabolic stability. The project resulted in the selection of the lead compounds 6n and 6o , which had antipsychotic profiles, combining dopamine D 2 -receptor and 5-HT 2A antagonism and metabolic stability.