Illicit use of cocaine (and other stimulants such as methamphetamine) continues to be a major health problem in the United States. No effective pharmacotherapy exists for cocaine or stimulant abuse. I propose to address this problem by developing site-directed cocaine abuse treatment agents which will attenuate the addictive and highly pleasurable effects of cocaine which are mediated at dopamine (DA) nerve terminals in the brain. The purpose of the work described here is to synthesize and preclinically evaluate compounds which interact with the cocaine binding site on the dopamine transporter as potential therapeutic agents for abuse of cocaine (and possibly other stimulants). The desired compounds will act as either long lasting, slow onset agonists, or partial agonists, mixed agonists/antagonists or full antagonists for the reinforcing properties of cocaine. Reversibly binding derivative of bicyclic [2,2,1] and [2,2,2] have been of interest because they combine the potency and selectivity of the GBR class of drugs in a molecular structure bearing more similarity to cocaine. Modification of the structure (stereochemistry, substituents on the bicyclic and phenyl ring, type of amine, etc.) Of 2-phenyl-3-(aminomethyl)-bicycloalkanes introduces the possibility of an easy to synthesize rigid framework onto which a myriad of substituents can be placed. This framework will be used to fine tune the activity of these compounds ranging from cocaine agonists to antagonists. I propose to install a ketone functionality onto the bicyclic system by cycloannulating -(N,N-dimethylamino)styrene and cyclohex-2-en-1-one. The resulting isomeric mixture of phenyl-amino bicycloalkanones will be separated, reduced and further esterified. The incorporation of a ketone functionality onto the bicyclic system will enhance not only the water solubility by increasing the polarity of the hydrophobic face, but it will also allow for elaboration of the structure to prepare a wide array of derivatives required to further explore binding to the dopamine transporter site. These analogs will be evaluated alone and in combination with cocaine for potential as cocaine treatment agents utilizing rat striatal tissue or synaptosomes. These tests will include (but are not necessarily limited to): In vitro inhibition of [3H]WIN 35,428 binding and [3H]DA uptake will be measured on all compounds in order to test both their ability to inhibit cocaine binding and to inhibit the uptake of dopamine. In vitro inhibition of [3H]paroxetine and [3H]nisoxetine binding will be measured on most compounds to establish their relative selectivity for the various transporters. Analysis of the structural changes will allow for the development of structure activity relationships related to the fit of those compounds in the dopamine transporter site. Results of these assays will direct us in the choice of new target molecules in this series. The synthetic work described above will be performed at the Georgia Institute of Technology under the supervision of Drs. Collard and Deutsch. In collaboration with Dr. Michael Kuhar, pharmacological testing will take place in the Yerkes Primate Center at Emory University.
