Novel (bisarylmethoxy)butylpiperidine analogues as neurotransmitter transporter inhibitors with activity at dopamine...

A series of (bisarylmethoxy)butylpiperidine derivatives was prepared and evaluated in vitro and in vivo to determine the structural requirements necessary for dual activity at the DAT and DA/5-HT receptor sites. These hybrid ligands, constructed by combining pharmacophores specific for the DAT and DA/5-HT receptors, could be useful drugs for treating cocaine addiction by assisting cocaine addicts in maintaining abstinence. The series was evaluated in vitro for DAT and DA/5-HT receptor activity and then selected compounds were tested in vivo for their effects on cocaine-induced hyperlocomotor activity (LMA). The majority of the new compounds demonstrated high to moderate affinity (4-191 nM) for the DAT with 4-hydroxy-4-phenylpiperidine analogues 14 and 15 possessing the greatest affinity. Compounds 15 and 22 exhibited the highest ratio of reuptake inhibition-to-binding (discrimination ratio, DR), 111 and 323, respectively. These derivatives had modest affinity and antagonistic activity for dopamine D(2)/D(3) receptors. Compounds 9 and 15 (DR=0.9 and 111, respectively) stimulated locomotor activity, whereas the other compounds suppressed this response. All compounds tested except for 17 and 21 attenuated cocaine-induced hyperlocomotion.