Design, synthesis, and biological evaluation of novel non-piperazine analogues of 1-[2-(diphenylmethoxy)ethyl]- and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines as dopamine transporter inhibitors

A series of novel diamine, amine-amide, and piperazinone analogues of N-[2- (bisarylmethoxy)ethyl]-N'-(phenylpropyl)piperazines, GBR 12909 and 12935, w ere synthesized and evaluated as inhibitors of presynaptic monoamine neurot ransmitter transporters. The primary objective of the study was to determin e the structural requirements for selectivity of ligand binding and potency for neurotransmitter reuptake inhibition. In general, the target compounds retained transporter affinity; however, structural variations produced sig nificant effects on reuptake inhibition and transporter selectivity. For ex ample, analogues prepared by replacing the piperazine ring in the GBR struc ture with an N,N'-dimethylpropyldiamine moiety displayed enhanced selectivi ty for binding and reuptake inhibition at the norepinephrine (NE) transport er site (e.g. 4 and 5). Congeners in which the amide nitrogen atom was atta ched to the aralkyl moiety of the GBR molecule showed moderate affinity (K- i = 51-61 nM) and selectivity for the dopamine transporter (DAT) site. In c ontrast, introduction of a carbonyl group adjacent to either nitrogen atom of the piperazine ring (e.g. 25 and 27) was not well tolerated. From the co mpounds prepared, analogue 16 was selected for further evaluation. With thi s congener, locomotor activity induced by cocaine at a dose of 20 mg/kg was attenuated with an AD(50) (dose attenuating cocaine-induced stimulation by 50%) of 60.0 +/- 3.6 mg/kg.