Phenyltropane

Phenyltropanes (PTs) were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. Although RTI holds a strong position in this field, they are not the only researchers that have prepared these analogues. This research has spanned beyond the last couple decades, and has picked up its pace in recent times, creating numerous phenyltropanes as research into cocaine analogues garners interest to treat addiction.

The phenyltropane compounds were initially discovered by R. Clarke et al. during research to try and dissociate the stimulant properties of cocaine from its abuse and dependence liability. The first simple phenyltropanes to be made (WIN 35065-2 and WIN 34,428) were shown to be active in behavioral assays only for the ββ-isomers. The activity of the corresponding αβ-isomers was disappointing.

It was later shown that WIN 35065-2 and WIN 34,428 are mostly dopamine selective reuptake inhibitors with some residual actions at the norepinephrine transporter (NET) and serotonin transporter (SERT). The neurotransmitter dopamine is a key candidate for explanation of reinforcing actions drugs. It's unclear to which extent NET is involved in the reinforcing actions of cocaine (an SNDRI). Animal studies show evidence that inhibiting the SERT might reduce cocaine intake.

Animal studies on monkeys and rats have tried to assess the self-administration propensity of phenyltropane analogs alongside cocaine. Frequently the analogs are administered prior to the start of a session to see if they can suppress cocaine lever responding. Most of the analogs behave in ways that might be considered typical for a DRI. In particular, they tend to stimulate locomotor activity, and cause nonselective reductions in cocaine intake relative to food. At the dose that can reduce cocaine intake, most of the analogs require a high DAT occupancy. This would mean that the agonists would need to be behaviorally active at the dose that can bring about reductions in cocaine craving. Most of the analogs will readily substitute for cocaine, although most do not elicit as many lever responses per session because of pharmacokinetic factors. Since these agonists function as reinforcers, there is an obvious concern surrounding their abuse liability.

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