New N-(benzhydryloxyalkyl)-4-(carboxy/carbamoylmethyl) piperidine derivatives with antidepressant activity

Several benzhydryloxylalkylpiperidine derivatives were prepared with the aim of obtaining new antidepressant compounds. The influence of the length of the aliphatic chain and of aromatic and piperidine ring substitutions was studied. The pharmacological activity of compounds was investigated in vivo by means of a screening comprising four pharmacological tests: antagonism of reserpine and apomorphine hypothermia; increase of yohimbine induced mortality; and antagonism of immobility in tail suspension test. An in-depth pharmacological study was performed with the more active compounds and a binding study to serotonin (5-HT), norepinephrine (NE) and dopamine (DA) reuptake sites was performed for the preferred compounds. The most active compounds [+], [-]-cis-31, 32 and 46 exhibited an interesting psychopharmacological profile after intraperitoneal administration. This profile was confirmed by the oral route for 31 and 46. In vitro, these compounds showed a non-selective inhibition of DA, NE and 5-HT uptake.