NOVEL GBR ANALOGS FOR THE TREATMENT OF COCAINE ABUSE

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Ethylenediamine derivatives with N-phenylalkyl and diphenylmethoxyethyl substituents represent truncated analogs of the GBR series. Based on in vitro pharmacology experiments the amine-amide derivatives of these analogs were shown to be attractive candidates for development as cocaine antagonists (or partial agonists) for the medication of cocaine addiction. In order to identify lead candidates for further in vivo behavioral studies the applicant plans to perform rationally directed structure-activity studies to optimize the pharmacological properties of these analogs. The aims are: 1) Identify the structural aspects in the N-phenylalkyl tail portion of the analogs to identify those changes that result in improved bidding to the dopamine transporter and reduced inhibition of dopamine reuptake; 2) Explore the effects of transposition of the carbonyl group in the bridge portion of the amine-amides to identify analogs with optimum pharmacological activity, 3) Further modify the diphenylmethoxy head group to increase the aqueous solubility of selected analogs, and 4) Pharmacologically characterize the analogs prepared for their affinity and uptake inhibition at the monoamine transporters. The lead compounds developed in this work will be further characterized during Phase II studies to afford effective medications for the treatment of cocaine abuse. PROPOSED COMMERCIAL APPLICATION: There are currently no medications for treating cocaine addition. The successful completion of the work proposed here should lead ultimately to the marketing of a drug for the treatment of chronic cocaine addition. The compounds may additionally be useful for the treatment of acute cocaine intoxication.