Substituted 2-(1,2,3,4-tetrahydroisoquinoline)-butyl derivatives of azaspiro[4.5]decane-7,9-dione and phthalimide as new 5-HT1A and 5-HT2A receptor ligands

Two series of 2-butyl-8-azaspiro[5,4]decane-7,9-dione (a) and N-phthalimido butyl (b) derivatives of 1,2,3,4-tetrahydroisoquinoline (THIQ) were synthes ized. The impact of substituent variations in the aromatic part of the THIQ moiety on 5-HT1A and 5-HT2A receptor affinities, as well as in vivo functi onal properties of the investigated compounds are discussed. It was found t hat those modifications improved 5-HT2A receptor affinity, but also slightl y reduced the binding affinity for 5-HT1A receptors (in comparison with the unsubstituted THIQ derivatives 3a and 3b). The most active compound (8-Br, 5-OCH3-THIQ - 8a) showed features of a 5-HT1A (postsynaptic)/5-HT2A recept or antagonist. Additionally, all chloro derivatives with high and equal aff inity for 5-HT1A receptors revealed different functional properties, i.e. a n agonistic activity of presynaptic 5-HT1A receptors (4a) and a partial ago nistic activity of postsynaptic 5-HT1A receptors (4a, 6a) or an antagonisti c activity of postsynaptic ones (5a).