Locomotor stimulant effects of novel phenyltropanes in the mouse

With the hypothesis that 3-phenyltropane analogs of cocaine might be useful as cocaine medications, 17 analogs (RTI-51, RTI-55, RTI-108, RTI-112, RTI- 113, RTI-116, RTI-120, RTI-121, RTI-126, RTI-139, RTI-141, RTI-150, RTI-171 , RTI-177, RTI-199, RTI-204, and RTI-219) were characterized for their pote ncy and selectivity at the monoamine transporters in a previous study. Base d on their affinities to the transporters in this earlier study, the analog s were classified as nonselective (cocaine, RTI-51, RTI-55, RTI-108, RTI-11 2. RTI-116, RTI-126, and RTI-139) or dopamine transporter (DAT) selective ( RTI-113, RTI-120, RTI-121, RTI-141, RTI-150, RTI-171, RTI-177, RTI-199, RTI -204, and RTI-219). In the present study, the locomotor stimulating effects of these analogs were compared to those of cocaine to obtain a measure of in vivo activity. Each analog was more potent than cocaine in the in vivo a ssay, as observed in the earlier in vitro studies. Most of these compounds were as efficacious as cocaine, but RTI-51. RTI-108, RTI-113, RTI-121, RTI- 139, RTI-141, RTI-177, RTI-204, and RTI-219 were longer acting. Although no correlation between chemical structure and transporter selectivity was fou nd, the short-acting DAT-selective analogs, RTI-120, RTI-150, RTI-171, and RT1-199, all contained a methyl group in the X position of the WIN 35,065-2 molecule. The positive correlation of the IC(50)s for the DAT to potencies for increasing locomotor activity suggested that binding to DAT was respon sible for some, if not most, of the locomotor effects of these compounds. S everal compounds, including RTI-113 and RTI-177, exhibited properties ideal for medications for cocaine abusers, such as an equivalent efficacy, a hig her potency, and a longer duration of action as compared to cocaine. (C) 20 01 Elsevier Science Ireland Ltd. All rights reserved.