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Title: The potential role of cyclic nucleotides and membranes on the action of neuroleptic drugs
Author: El-Shazly, H. M.
Awarding Body: University College of Swansea
Current Institution: Swansea University
Date of Award: 1995
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Six drugs currently used in the treatment of schizophrenia were examined for their effects upon membranes and second messenger related enzymes. The drugs investigated in this thesis were selected on the basis of their pharmacological effects and the extent of their side effects. The effects of these drugs on the membranes and enzyme activity of Ca-ATPase, adenylyl cyclase and phosphodiesterase were studied, using different techniques, and an attempt was made to establish whether the effects of drugs exerted on the enzyme activities are direct or indirect i.e. as a result of alterations in the membrane fluidity, hence correlating the two phenomena. Chlorpromazine and trifluoperazine had ordering effects on artificial membranes at clinically therapeutic concentrations. Phosphorescence polarisation measurements indicated restrictions in protein mobility and aggregation as concentrations of these two drugs increased, hence supporting the previous observations. Meanwhile, sulpiride, remoxipride and procyclidine did not cause any apparent changes on the membrane fluidity, yet remoxipride still demonstrated a degree of restriction in the protein mobility, indicating a direct interaction of drug with the protein. While investigation of the effects of clozapine on membrane were not successful, the octanol/buffer partition coefficient obtained, suggests that clozapine partitions into the membrane. Similar observations, as remoxipride, were obtained for the phosphorescence polarisation measurements, again suggesting a direct interaction with the protein. Chlorpromazine and trifluoperazine were found to be potent inhibitors of enzyme activity. Sulpiride, remoxipride and procyclidine also inhibited the enzyme but to a much lesser extent than chlorpromazine and trifluoperazine. Clozapine demonstrated a general inhibition of the enzyme activities, although an initial stimulation was observed for Ca-ATPase and adenylyl cyclase of rat brain and liver at low concentrations. These data are discussed in the content of recent research into the action of these drugs.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available