The purpose of this work is to synthesize and evaluate compounds which interact with the stimulant binding site(s) on the dopamine transporter, with the aim of identifying compounds which are antagonists for the reinforcing and/or psychotogenic properties of cocaine. The current program to synthesize and evaluate compounds which bind irreversibly to sites on or related to the dopamine transporter will be continued. This program involves substitution of phencyclidine, GBR-1 2783 (""""""""GBR""""""""), dopamine, methylphenidate and mazindol, with electrophilic groups such as isothiocyanate, maleimide, bromoacetyl, and fluorosulfonyl. This work has been successful in identifying a phencyclidine (Fourphit) which antagonizes the stimulant effects of cocaine. Completion of this program will benefit drug research by expanding the available data base on which to search for features which distinguish compounds which act as effective cocaine antagonists. In addition, similar derivatives of LR5182, a compound with some structural similarities to cocaine, but higher selectivity and affinity for the dopamine transporter, will be synthesized. Several lines of evidence suggest that there may be more than one substrate and/or stimulant binding site per dopamine transport complex. Based on such a model, the effects of linking two dopamine molecules together and varying the distance of separation will be explored. As a variation of the above theme, a GBR derivative with two reactive groups in the same molecule will be synthesized and the tritiated form will be used in protein isolation and characterization studies. The mutual inhibition of GBR, methylphenidate and cocaine binding suggests that derivatives of these stimulants may serve as antagonists or partial agonists for cocaine. Methylphenidate has structural analogies with cocaine, but appears to have a much lower abuse potential; methylphenidate derivatives may have promise as """"""""partial agonists"""""""". The SAR that has been gained about cocaine will be applied to methylphenidate, with the aim of producing more metabolically stable compounds with higher affinity. The need for more soluble and less lipophilic GBR-derivatives has become apparent; these type of derivatives might have improved potential as therapeutic agents. The use of epoxides as electrophiles specific for sulfhydryl groups will be tested with the synthesis of the 3-epoxide derivative of GBR-12783. The effect of the newly synthesized compounds on the dopamine transport complex will be determined by examining their ability to inhibit [3H]-CFT binding and [3H]-dopamine transport in vitro. Compounds which prove to be irreversible inhibitors of stimulant binding, exhibit increased affinity for the transporter, or possess novel pharmacological properties in the in vitro screening above will then be submitted to NIDA for both in vitro and in vivo analysis using the NIDA/SRI protocol. Selected compounds from those identified above will be tested for their ability to antagonize the behavioral effects of cocaine and other stimulants in our established rat models; [3H]-CFT binding will be determined ex vivo in striatal tissue from the same animal. Two different behavioral paradigms will be used,in order to better correlate binding and behavior.
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