D3 Receptor Compounds for the Treatment of Psychostimulant Abuse. This application is submitted in response to RFA-DA-07-006 entitled Design, Synthesis, and Preclinical Testing of Potential Treatment Agents for Drug Addiction. This research proposal describes the a) synthesis, b) in vitro pharmacological characterization and c) in vivo evaluation of novel D3 dopamine receptor selective antagonists, partial agonists and agonists as potential therapeutic agents for the treatment of cocaine abuse. Our hypothesis is that stimulation of the D3 dopamine receptor in the nucleus accumbens plays a pivotal role in the reinforcing properties of psychostimulants. We further hypothesize that D3 dopamine receptor subtype selective compounds have potential as a new generation of D3 receptor-based pharmacotherapeutics for the treatment and/or management of individuals who abuse psychostimulants. Because of the high degree of homology between the binding sites of the D2 and D3 dopamine receptor subtypes, it has been difficult to develop authentic D3 receptor selective compounds. However, we have recently identified a panel of substituted phenyl-piperazine compounds that are >30-fold selective for the D3 dopamine receptor subtype with varying degrees of intrinsic activity. Therefore, we are beginning to understand how the structure of these compounds influences binding and functional selectivity at D2 and D3 dopamine receptor subtypes .
In Aim 1 we will synthesize a panel new compounds as part of our continuing goal to generate compounds which maximize D3 receptor selectivity while a) minimizing log P values (<3.0), which are predictive of a drug's ability to cross the blood brain barrier and b) having varying ability to active several different signaling pathways (functional selectivity).
In Aim 2 we propose to undertake an in vitro pharmacological assessment of the binding and intrinsic activity of D3 selective compounds. This will include compounds from previous studies and the limited number of new compounds (Aim 1) Our novel compounds will be evaluated for intrinsic activity at both D2 and D3 receptors using a) binding assays to examine selectivity for high and low affinity states, b) an adenylyl cyclase inhibition assay, c) a GIRK electrophysiology assay and d) a mitogenic assay.
In Aim 3 we will evaluate the in vivo efficacy of our novel compounds for the ability to attenuate the a) psychostimulant-dependent increased locomotor activity and b) self-administration of cocaine. Both fixed ratio (FR) and a progressive ratio (PR) schedules will be used. In addition, compounds will be examined for their effects on reinstatement of extinguished cocaine-seeking behavior. The overall goal of this research project is to determine a) the structural elements of our compounds that determine binding and functional selectivity and b) which functional property/properties are predictive of behavioral efficacy in the rodent model of drug addiction.
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