Synthesis and 5-HT1A, 5-HT2A receptor activity of new β-tetralonohydantoins

A series of new 3-[4-(4-arylpiperazinyl)-butyl]-β-tetralonohydantoins (8a-13a) were synthesized. The compounds exhibited high affinity for 5-HT1A receptors (Ki = 6 to 55 nM) combined with moderate-to-high 5-HT2A receptor affinities (Ki = 45 to 213 nM). The results of in vivo studies indicated that of the compounds tested, 3-[4-(4-phenylpiperazinyl)-butyl-β-tetralonohydantoin (8a) showed features of full (pre- and postsynaptic) 5-HT1A receptor agonists, whereas compounds 9a-13a behaved like antagonists of postsynaptic 5-HT1A receptors; additionally, compound 13a produced an effect characteristic of presynaptic 5-HT1A receptor agonists. Moreover, compounds 8a and 10a-13a exhibited properties of 5-HT2A receptor antagonists. Due to the most interesting 5-HT1A/5-HT2A functional profile compounds 8a and 13a were further tested for their potential psychotropic activity. In fact, compound 8a (but not 13a) showed diazepam-like anxiolytic activity and behaved like a weak antidepressant.