Enhancing a CH-π Interaction to Increase the Affinity for 5-HT1A Receptors

An electrostatic interaction related to a favorable position of the distal phenyl ring and a phenylalanine residue in the binding pocket would explain the higher 5-HT1A affinity of a 4-phenyl-1,2,3,6-tetrahydropyridine (THP) analogue compared to the corresponding 4-phenylpiperazine analogue. To explore a possible reinforcement of this interaction to increase the affinity for 5-HT1A receptors, different 4-substituted-phenyl analogues were synthesized and tested. The most important increase of affinity is obtained with two electron-donating methyl groups in positions 3 and 5.