Extensive research suggests that cocaine's abuse potential is associated with direct binding and inhibition of the DA transporter. Our proprietary compound, PD2007 is a high affinity DA transport inhibitor that possesses several important characteristics of an ideal cocaine therapeutic. PD2007 has a 10-fold higher affinity for the DA transporter than cocaine. PD2007 is lipophilic consistent with good penetration into brain which has been confirmed in pharmacokinetic studies indicating that PD2007 is concentrated in brain at several fold higher concentrations than cocaine. These same pharmacokinetic studies indicated that PD2007's half-life in brain was 14-fold longer than cocaine (PD2007 brain half-life = 8.5 hr). PD2007's 8.5 hr brain half-life is an ideal characteristic in a cocaine therapeutic that would allow practical dosing regimes. PD2007 cocaine-discrimination studies and conditioned place preference studies indicate that PD2007 has little or no abuse potential. And most importantly, Preliminary Studies indicate the pretreatment with 10 mg/kg PD2007 completely blocked the stimulant effects of cocaine. The proposed SBIR Phase 1 studies will determine if pretreatment with PD2007 blocks cocaine self-administration and whether PD2007 is self-administered, our Specific Aims are:
Specific Aim 1 A. Determine if PD2007 pretreatment selectively depresses the cocaine dose- response curve in rats.
Specific Aim 1 B. Determine if PD2007 is self-administered in rats.
Specific Aim 1 C. Determine if PD2007 pretreatment selectively depresses the cocaine dose- response curve in monkeys.
Specific Aim 1 D. Determine if PD2007 is self-administered in monkeys. In the present application, we propose preclinical studies to assess whether our propriety compound, PD2007, is an effective cocaine therapeutic in preclinical studies. Specifically, we will determine if our dopamine transport inhibitor, PD2007, blocks cocaine self-administration in both rats and monkeys. An additional important property of a cocaine therapeutic is that the compound does not demonstrate significant abuse liability itself. We will assess the abuse liability of PD2007 by determining whether PD2007 is self-administered in both rats and monkeys. It is anticipated that PD2007 will block cocaine self-administration in both species and demonstrate little or nor abuse potential. Such results would indicate that PD2007 is a prime candidate for further preclinical development as a cocaine therapeutic. ? ? ?
