Dual NK1 antagonists—serotonin reuptake inhibitors as potential antidepressants. Part 2: SAR and activity of benzyloxyphenethyl piperazine derivatives

The synthesis, structure–affinity relationship and activity of benzyloxyphenethyl piperazine derivatives combining NK1 antagonism and serotonin reuptake inhibition is described. Compound 7u was shown to be active in animal models of 5-HT reuptake inhibition and central NK1 receptor blockade, and was demonstrated to be orally active in an integrated model sensitive to both mechanisms. This class of compounds potentially represents a new generation of antidepressants.