The National Institute of Drug Abuse has indicated, """"""""NIDA's top research priority is to find a medication to block or greatly reduce the effects of cocaine to be used as part of a comprehensive treatment program."""""""" The purpose of the present FAST TRACK Phase 1 application is to continue development of our proprietary dopamine (DA) transport inhibitor, PD2005, as a cocaine therapeutic. Extensive research shows that the abuse potential of cocaine is due to direct binding and inhibition of the DA transporter in brain. While most drugs that inhibit the DA transporter are drugs of abuse (e.g. cocaine, amphetamine) benztropine is the exception. Benztropine was FDA approved 40 years ago for treating Parkinson's Disease and is not abused. Unfortunately, benztropine has significant anticholinergic M1 side effects that preclude its use as a cocaine therapeutic. A benztropine analog, PD2005, has been synthesized that has no high affinity M1 binding while demonstrating high affinity for the DA transporter. Further, PD2005 has a slow onset of action that minimizes abuse potential, PD2005 has a long duration of action which allows practical dosing regimes, and PD2005, unlike cocaine, is not self-administered in monkeys indicating little or no abuse potential. Proposed Phase 1 studies will determine if pretreatment with PD2005 blocks cocaine self-administration in monkeys - a critical property for potential cocaine therapeutic. We propose:
Specific Aim lA: Optimize the current PD2005 synthetic method for commercial production and synthesize PD2005 under Good Laboratory Practice Conditions. Succesfully manufactured GLP drug is required by FDA for proposed FAST TRACK Phase 2 studies.
Specific Aim 1 B: Determine if PD2005 depresses the cocaine self-administration dose-response curve in monkeys.
Specific Aim 1 C. Determine if PD2005 selectively depresses the cocaine dose-response curve by determining the effect of PD2005 pretreatment on operant responding in monkeys maintained by food reinforcement.
