The chemical structure of phenothiazine provides a most valuable molecular template for the development of agents able to interact with a wide variety of biological processes. Synthetic phenothiazines (with aliphatic, methylpiperazine, piperazine-ethanol, piperazine-ethyl, or piperidine side-chain) and/or phenothiazine-derived agents e.g., thioxanthenes, benzepines, imonostilbenes, tricyclic antidepressants, dimetothiazine, and cyproheptadine have been effective in the treatment of a number of medical conditions with widely different etiology. These include various currently clinically used drugs for their significant antihistamic, antipsychotic, anticholinergic (antiparkinson), antipruritic, and/or antiemetic properties. They are also employed, although to a minor extent, as antidepressants, antispasmodics, analgesics, and antiarrhythemics. Some of these agents are also useful as anti-inflammatory, coronary vasodilator, radioprotective, sedative, antitussive, and skeletal muscle-relaxing medication. Still, others show different degrees of effectiveness as antibacterials, anthelmintics, antimalarials, or local anesthetics; a few are valuable in the control of acute migraine attacks and intractable hiccough. Adding to the seemingly ever-expanding therapeutic use of phenothiazine derivatives, a number of "old" and newly synthesized compounds e.g., "half-mustard-type" and benzo[alpha]phenothiazines, appear to be helpful as multidrug resistance modifiers, a property of particular importance in cancer chemotherapy. Some phenothiazines inhibit human plasmatic leucine-enkephalin aminopeptidase(s), enzymes known to regulate the turnover rate of a wide range of bioactive substances. These findings could lead to the design of new therapeutic treatment modalities for conditions such as Alzeimer's and Creutzfeldt-Jakob disease. Hopefully, this work will help to the rational design of new and improved pharmacological approaches based on a better understanding of the correlation between chemical structure, pharmacodynamic properties, and pharmacological activity of various phenothiazines and phenothiazine-derived classes of drugs.

SYNOPSIS Migraine patients, either during an attack or when pain‐free, have significantly higher platelet‐rich and platelet‐poor plasma methionine‐enkephalin levels than healthy race‐ and sex‐matched and age‐comparable controls. Although we did not observe differences in the platelet‐rich samples between the patients subgroups, platelet‐poor samples had higher peptide levels during a pain‐free period than the values obtained for the patients during a migraine episode. Similarly, platelet‐rich samples obtained from controls and patients during an attack had higher methionine‐enkephalin levels than their corresponding platelet‐poor plasma samples. These results provide new evidence supporting the involvement of the endogenous peptides in the etiology of migraine headache and suggest that plasma methionine‐enkephalin levels could serve as a biological marker for this condition.

SYNOPSIS Plasma methionine‐enkephalin (MET) levels in migraine patients, either during an attack or when pain‐free, are statistically significantly higher than in matched controls; this is also true when comparing the classical and nonclassical migraine subpopulations with the control group. Individual patients consistently presented lower MET plasma concentrations in the pain‐free period than during the acute headache, with some subjects showing values falling within the range of controls. Platelet neuropeptide content was similar in patients and controls, irrespective of plasma MET levels. These results indicate that increased plasma MET concentrations are associated with the occurrence of a migraine episode and suggests that they are not a constant characteristic of migraineurs.