Neurochemical studies on the substituted benzamides : a novel group of dopamine receptor antagonists

Freedman, Stephen Barry (1981) Neurochemical studies on the substituted benzamides : a novel group of dopamine receptor antagonists. University of Southampton, Doctoral Thesis.

Abstract

A study has been made of the interaction of a novel group of neuroleptics, the substituted benzamides, with the central nervous system (C.N.S.). Sulpiride, the most important member of this group, has pronounced antidopaminergic activity in a number of pharmacological tests yet is completely inactive on the doiamine sensitive adenylate cyclase. This distinct pharmacological profile has led to the proposal of a novel mechanism of action for sulpiride, including the recent suggestion by Kebabian and Calne that multiple dopamine receptors exist in the C.N.S. They proposed that sulpiride was a specific antagonist at one of these receptors. This study h..s utilised 3H-sulpiride in radioreceptor binding studies to investigate the molecular interaction of sulpiride with the C.N.S. and to examine previously suggested theories as to the mechanism of action of sulpiride. 3H-Sulpiride was found to bind to a saturable, high affinity and stereospecific binding site in selected areas of the C.N.S. known to have a dopaminergic inneraation. Pharmacological specificity of this site indicated a high affinity for all major classes of neuroleptic drugs, substituted benzamides and dopamine receptor agonists, which together with the absence of an interaction with non-dopaminergic drugs, suggests a highly selective interaction with dopamine receptors. This distinguished sulpiride from other neuroleptic agents. Selective lesioning studies in the corpus striatum indicate that the anatomical location of 3H-sulpiride binding is similar to that of classical neuroleptics, with binding sites on both striatal intrinsic neurones and the corticostriatal pathway. In addition, guanine nucleotides were found to alter the affinity of dopaminergic agonists for the 3H-sulpiride binding site. This was specific in that only GTP, GDP and Gpp(NH)p produced the response and that antagonist binding was not affected. These findings are not compatible with the suggestion by Kebabian and Calne, that sulpiride interacts only with a subpopulation of non cyclase linked dopamine receptors. Since sulpiride, unlike other neuroleptics, was found to exhibit an absolute dependence on sodium ions for activity, it was decided to investigate this phenomenon in order to try to explain some of the anomalies of sulpiride action. Other studies have determined that an essential sulfhydryl group is located on, or close to, the 3H-sulpiride binding site. Evidence was found that, in the presence of sodium ions, an allosteric transition of the binding site occurs, making this essential sulfhydryl group less accessible to modification by N-ethylmaleimide. These results have been discussed with reference to several previously suggested models for the mechanism of action of sulpiride. However, because of lack of support for these ideas, several alternative hypotheses have been proposed in the light of current developments in dopamine receptor pharmacology.

This record has no associated files available for download.

Contributors

Download statistics