Phenothiazines binding

Hf and H Receptors. Histamine exerts its actions by binding to receptors on cell membranes. Two types of histamine receptors, the Hi and H2 receptors, are known specific agonists and antagonists exist for each of these receptors. Black et al. (55) differentiated H and H2 receptors with the compounds, 2-methylhistamine and 4 methylhistamine. 2-Methylhistamine is active on tissues with H receptors 4-methylhistamine is active on tissues with H2 receptors. Classical antihistaminic drugs were developed in the 1930 s these compounds block H but not H2 receptors. Among the clinically used H -blockers are derivatives of ethanolamine, ethylenediamine, alkylamine, piperazine and phenothiazine (32). These agents are valuable in the treatment of... 

It also seems plausible that antipsychotic drugs competitively bind with dopamine receptors and block the action of dopamine on corresponding receptor sites, thus lowering psychotic activity. Central dopamine receptors are subdivided into Dj, D2, and according to some sources, Dj receptors. These receptors have a high affinity for dopamine, but they differ in sensitivity to neuroleptics of various chemical classes. For example, drugs of the phenothiazine series are nonselective competitive Dj and D2 antagonists. Unlike phenoth-iazines, antipsychotics of the butyrophenone series such as haloperidol display selective action only on D2 receptors. 

Multiple drug interactions can occur with the TCA drugs. Because of their high degree of binding to plasma proteins, competition for binding sites can exist between TCAs and phenytoin, aspirin, phenothiazines. 

Mechanism of Action A phenothiazine that antagonizes dopamine neurotransmission at synapses by blocking postsynaptic dopaminergic receptors in the brain. Therapeutic Effect Decreases psychotic behavior. Also produces weak anticholinergic, sedative, and antiemetic effects and strong extrapyramidal effects. Pharmacokinetics Erratic absorption. Protein binding greater than 90%. Metabolized in liver. Excreted in urine. Half-life 33 hr. 

Mechanism of Action A phenothiazine derivative that blocks dopamine at postsynap-tic receptor sites. Possesses strong extrapyramidal and antiemetic effects and weak anticholinergic and sedative effects. Therapeutic Effect Suppresses behavioral response in psychosis reduces locomotor activity and aggressiveness. Pharmacokinetics Readily absorbed following PO administration. Protein binding 90%-99%. Metabolized in liver. Excreted in urine. Half-life 24 hr. 

In adults, TCAs are highly protein-bound medications. At any one time 75%-95% of the drug in the body will be bound to circulating ttj glycoprotein. Competition for binding sites on ttj glycoprotein by drugs such as aspirin, phenytoin, and some phenothiazines... 

Acetylsalicylic acid, phenytoin, phenothiazines Competition for binding to glycoprotein TCA toxicity (cardiac effects, delirium, sedation) due to increased amount of free TCA Lower TCA dose Baldessarini, 1996... 

The concept of abnormal proteins in CJD may provide insights useful for drug design. The pioneering (and Nobel Prize winning) work of Prusiner has enabled the preliminary identification of prototype agents as therapies for CJD. Preliminary work identified two classes of compounds with therapeutic potential polysulphated molecules and tricyclic molecules (e.g., phenothiazines, aminoacridines). These compounds bind to PrP and endeavor to inhibit the PrP to PrP cascade of conformational change. 

The antimalarial drug quinacrine and some phenothiazine derivatives, acepro-mazine, chlorpromazine, and promazine, have been used for the treatment of prion diseases (Doh-ura et al., 2000 Korth et al., 2001 May et al., 2003). The molecular mechanism associated with the inhibition of PrPsc formation by quinacrine remains unknown. However, it is proposed that quinacrine binds with human prion protein at the Tyr-225, Tyr-226, and Gln-227 residues of helix 3 (Vogtherr et al., 2003) and provides neuroprotection. Quinacrine may also act as an antioxidant and reduce the toxicity of prP 6 (Turnbull et al., 2003). 

The potassium channels present in neuronal membranes could also be affected by phenothiazine derivatives. In the study performed by Ogata et al. [255] it was shown that CPZ (9) interfered with several types of potassium channels present in membranes of neurons of the newborn rat cultured dorsal root ganglia. Reversible reduction of the amplitude was found for transient and delayed rectified K+ currents, while inward rectified K+ current remained unaffected by CPZ (9). The block of delayed rectified K+ current by CPZ (9) was, however, less potent than block of the transient one. The hyper-polarizing shift of the steady-state inactivation curve for transient K+ current indicated that CPZ (9) binds preferably to the channels in the inactivated state. 

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