Advances toward new antidepressants beyond SSRIs: 1-Aryloxy-3-piperidinylpropan-2-ols with dual 5-HT sub(1A) receptor antagonism/SSRI activities

A series of 1-aryloxy-3-piperidinylpropan-2-ols possessing potent dual 5- HT sub(1A) receptor antagonism and serotonin reuptake inhibition was discovered. 1-(1H-Indol-4-yloxy)-3-(4-benzo[b]thiophen-2-ylpiperidinyl)propan- 2 -ols exhibited selective and high affinities at the 5-HT sub(1A) receptor and serotonin reuptake site in vitro. In vivo evaluation of this series of compounds demonstrated elevated extracellular serotonin levels from the basal and quick recovery of neuron firing that was presumably suppressed by the initial acute activation of 5-HT sub(1A) somatodendritic autoreceptors.