Pyrrolidine Derivatives as New Ligands for 5-HT1A Receptors

Our research group has long been involved in the development of new 5-HT1A selective ligands and 1,3-dioxolane derivatives bearing a phenoxyethylamine basic portion in position 4 were reported1. They were shown to have interesting 5-HT1A agonist activity accompanied by a good affinity, even if a certain alpha1 affinity was still present. 5-HT1A agonists and partial agonists have proved useful in the treatment of neuropsychiatric disorders such as anxiety and depression, to prevent neurodegeneration and for their antinociceptive activity2,3. On this basis and with the aim to improve 5-HT1A affinity and selectivity, compound A derivatives have been synthesized. A frozen structure of the ethylamine portion characterizes the new ligand and this variation4 with respect to the lead A has been designed in order to decrease the flexibility of this part of the molecule (figure 1). Stereospecific synthesis has been planned to give the desired four enantiomers (figure 1) so that it has been evaluated: 1. the effect on 5-HT1A affinity of the molecular rigidity provided by pyrrolidine core in comparison to that of the lead compound A; 2. stereoisomeric preferences for the receptor interaction. Several reactions and different synthetic schemes have been followed to obtained these four stereoisomers with good yield and a process optimization has been pursued. Structural characterization by NMR and mass (Q-TOF) analysis have been performed on the final compounds together with their optical purity determination.