5HT1a Receptor Binding Affinities of a Series of Serotonin Transporter (SERT) Inhibitors and Related Thermodynamic Insights^

Clinical depression encompasses a complex neurobiology involving multiple interacting systems. This intricate pathophysiology is, in part, correlated with dysfunction in serotonin (5HT) neurochemistry. The 5HT1a receptor (R) and SERT (serotonin transporter) components of this network are highly correlated to mood and anxiety regulation and difficulties in this regard in the realm of depression.

Aims: The current study was designed to develop a series of arylpiperazine derivatives ligands that are antagonists at both H5HT1aR and SERT.

Study Design: Development of new chemotype antagonists at H5HT1aR and SERT.

Place and Duration of Study: University of Catania (Italy) and University of Montana, Missoula, Montana, May 2008 to June 2013.

Methodology: Chinese Hamster Ovary cells transfected with the gene for the Human (H) 5HT1a Receptor were cultured, and membranes containing the receptor were prepared for competition assays between the test compounds and the agonist, [3H]8-OH-DPAT. For thermodynamics, Ki's were determined at a series of temperatures from 0-35 degrees C. Further, membranes from rat brain were utilized for competition assays between the test compounds and the SERT inhibitor, [3H] paroxetine.

Results: Many of these substances show nanomolar affinities at H5HT1aR, and a number of the compounds also have high efficacy in inhibiting SERT. It is of note that some members of this series also substantially discriminate between binding at H5HT1aR and H5HT7R, a receptor studied with these compounds in previous work. Thermodynamic properties for the compound 4-[4-(3-benzo [b] thiophen-3-yl-3-oxopropylamino) piperidin-1-yl] benzonitrile (BTPN; compound15) are also reported.

Conclusions: There are a few of these compounds that excel in all three categories of H5HT1aR affinity, SERT inhibitory activity, and discriminatory binding capacity between the two receptors. Implications in the context of clinical needs in depression and other nervous systems disorders are discussed.