Enhancing a CH−π Interaction to Increase
the Affinity for 5‑HT<sub>1A</sub> Receptors
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Abstract
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-HT<sub>1A</sub> 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-HT<sub>1A</sub> 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
