Identification and characterization of the cocaine receptor in the CNS is a necessary step toward the development of efficacious treatment agents for cocaine abuse. Preliminary evidence suggests that the high affinity [3H] cocaine binding site in brain is associated with the dopamine (DA) transporter. The reinforcing properties of cocaine and cocaine analogs correlates with their potency of DA transport inhibition and affinity for the DA transporter site, implicating this site as the """"""""cocaine receptor"""""""". The specific identification and biochemical characterization of this receptor has not yet been achieved. One of the receptor site via photoactive radiolabeled ligands which upon photoincorporation would be covalently attached to the receptor.
The specific aim of this proposal is the development and pharmacologic testing of a number of radiolabeled photoaffinity ligands for the cocaine receptor. We have selected the aryldialkylpiperazine """"""""GBR12909"""""""" as a model compound from which to synthesize such a photoaffinity label because of its high affinity for the [3H] cocaine binding site and the DA transporter. Our laboratory has generated a limited number of pilot aryl azide GBR compounds which suggest that the production of a photoaffinity ligand for the cocaine receptor is feasible. We propose to generate and select GBR photoaffinity ligands with high affinity for the cocaine receptor which will be subsequently radiolabeled with 125I. We will utilize the [125I]GBR-N3 compound to identify the cocaine receptor by chromatographic and electrophoretic techniques. Selectivity and specificity of photoincorporation of the [125I]GBR-N3 will be evaluated as well as preliminary pharmacology and biochemistry of the labeled site to demonstrate it to be the cocaine receptor.