Serotonin (5-hydroxytryptamine, 5-HT) is one of the most attractive targets for medicinal chemists. Among 5-HTRs, the 5-HT(1A) subtype is the best studied and it is generally accepted that it is involved in psychiatric disorders such as anxiety and depression. Several structurally different compounds are known to bind 5-HT(1A)R sites. Among these, arylpiperazine derivatives represent one of the most important classes of 5-HT(1A)R ligands. This article will review the development of arylpiperazine derivatives acting at 5-HT(1A)Rs with an emphasis on structure-affinity relationships of agonists and antagonists, ligand-receptor interactions and pharmacological applications.

We present in this study an optimization of a preliminary pharmacophore model for 5-HT(7)R antagonism, with the incorporation of recently reported ligands and using an efficient procedure with the CATALYST program. The model consists of five features: a positive ionizable atom (PI), a H-bonding acceptor group (HBA), and three hydrophobic regions (HYD). This model has been supported by the design, synthesis, and biological evaluation of new naphtholactam and naphthosultam derivatives of general structure I (39-72). A systematic structure-affinity relationship (SAFIR) study on these analogues has allowed us to confirm that the model incorporates the essential structural features for 5-HT(7)R antagonism. In addition, computational simulation of the complex between compound 56 and a rhodopsin-based 3D model of the 5-HT(7)R transmembrane domain has permitted us to define the molecular details of the ligand-receptor interaction and gives additional support to the proposed pharmacophore model for 5-HT(7)R antagonism: (i) the HBA feature of the pharmacophore model binds Ser(5.42) and Thr(5.43), (ii) the HYD1 feature interacts with Phe(6.52), (iii) the PI feature forms an ionic interaction with Asp(3.32), and (iv) the HYD3 (AR) feature interacts with a set of aromatic residues (Phe(3.28), Tyr(7.43)). These results provide the tools for the design and synthesis of new ligands with predetermined affinities and pharmacological properties.

We have designed and synthesized a new series of arylpiperazines V exhibiting high 5-HT(1A)R affinity and selectivity over alpha(1)-adrenoceptors. The new selective 5-HT(1A)R ligands contain a hydantoin (m = 0) or diketopiperazine (m = 1) moiety and an arylpiperazine moiety separated by one methylene unit (n = 1). The aryl substituent of the piperazine moiety (Ar) consists of different benzofused rings mimicking the favorable voluminous substituents at ortho and meta positions predicted by 3D-QSAR analysis in the previously reported series I. In particular, (S)-2-[[4-(naphth-1-yl)piperazin-1-yl]methyl]-1,4-dioxoperhydropyrrolo[1,2-a]pyrazine [(S)-9, CSP-2503] (5-HT(1A), K(i) = 4.1 nM; alpha(1), K(i) > 1000 nM) has been pharmacologically characterized as a 5-HT(1A)R agonist at somatodendritic and postsynaptic sites, endowed with anxiolytic properties. Ligand (S)-9 is predicted, in computer simulations, to bind Asp(3.32) in TMH 3, Thr(5.39) and Ser(5.42) in TMH 5, and Trp(6.48) in TMH 6. We propose that agonists modify, by means of an explicit hydrogen bond, the conformation of Trp(6.48) from pointing toward TMH 7, in the inactive gauche+ conformation, to pointing toward the ligand binding site, in the active trans conformation.