Arylpiperazine derivatives of 3-propyl-β-tetralonohydantoin as new 5-HT1A and 5-HT2A receptor ligands

A series of new analogues of 3-[3-(4-arylpiperazinyl)-propyl]-cyclohexane-1',5-spirohydantoin (2), with aromatic ring fused in amide moiety (4-9) were synthesized and evaluated for affinity at 5-HT1A and 5-HT2A receptors. The influence of the substitution mode in the phenyl ring of phenylpiperazine moiety on the affinity for both receptors has been discussed. The most potent 5-HT1A (9, K-i = 53 nM) and 5-HT2A (4, 6, 8 and 9; K-i = 14-76 nM) ligands were evaluated in in vivo tests. The obtained results indicate that all in vivo tested compounds showed pharmacological profile of 5-HT2A antagonists. Additionally, a m-CF3 derivative (9), behaved like a partial agonist (agonist of pre- and antagonist of postsynaptic) of 5-HT1A receptors and may offer a new lead for the development of potential psychotropic agents.