Antihistamines discovery

The discovery of the antiulcer activity of H2 antihistamine antagonists has revolutionized the treatment of that disease. A benzimidazole. Omeprazole (55), inhibits gastric secretion and subsequent ulcer formation by a quite different mechanism. Studies at the molecular level suggest that this compound inhibits K /H dependent ATPase and consequently shuts down the proton pumping action of this enzyme system. 

Examples abound regarding the role of serendipity in the discovery of new therapeutic approaches, which on closer examination usually turned out to be the result of clinicians paying attention to unexpected clinical effects rather than discounting them. For example, lithium was tried first for hypertension, chlorpro-mazine was initially developed as an anesthetic, and imipramine was originally regarded as an antihistamine and an antipsychotic agent. Without astute clinical observations, these drugs would not have found their niche, nor would clozapine have been revived for the benefit of millions of the most difficult to treat schizophrenic patients. Other examples include the expanded indications of newer... 

After the discovery of drugs with antidepressant activity in the late 1950s, an intensive search was undertaken for pharmacological models that would provide an understanding of the therapeutic effects observed and at the same time assist in the development of other, still more effective and specific antidepressants. In pharmacological tests then available, the prototype imipramine showed sedative, antihistaminic and anticholinergic effects and thus did not differ fundamentally from other medicaments with no antidepressant activity, e.g. antihistamines. The following observations then led to a further step forward in the development of hypotheses ... 

Chlorpromazine s (CPZ) efficacy was discovered primarily by chance in exploratory clinical trials after it had been initially synthesized as an antihistamine. Its discovery, however, was not entirely fortuitous, because it was chosen for human investigation since it was mildly sedating. The concept of an antipsychotic, however, was unknown. CPZ s sedative properties then led the French anesthesiologist and surgeon Henri Laborit to use it in a lytic cocktail to reduce autonomic response with surgical stress (1). He also persuaded many clinicians to try it for the treatment of a wide variety of other disorders. In this context, he encouraged John Delay and Pierre Deniker (1952), who then administered CPZ to schizophrenic patients. The rest is history ( 2, 3). 

Tricyclic antidepressants—so called because of the characteristic three-ring nucleus—have been used clinically for four decades (Figure 30-1). They closely resemble the phenothiazines chemically and, to a lesser extent, pharmacologically. Like the latter drugs, they were first thought to be useful as antihistamines with sedative properties and later as antipsychotics. The discovery of their antidepressant properties was a fortuitous clinical observation. Imipramine and amitriptyline are the prototypical drugs of the class as mixed norepinephrine and serotonin uptake inhibitors though they also have several other properties. 

Another example is the discovery made during the use of the antihistamine promethazine to treat surgical shock. In order to improve potency, a chlorine atom was incorporated into the drug molecule. Subsequently, when the patients seemed to be unconcerned about undergoing surgery, chlorpromazine - the first... 

The first synthesis of phenothiazine was reported by Bernthsen about 80 years ago. In the evolution of the chemistry of this heterocycle, three periods can be discerned. First, phenothiazine was of interest owing to its quinonoid derivatives—an important chapter in sulfur dye chemistry. Research work in the field of phenothiazine was then stimulated by the discovery of the anthelmintic action of unsubstituted and of some C -substituted phenothiazines. During the last two decades, the exceptional pharmacological properties of some A-substituted phenothiazines, e.g., the antihistaminic activity of promethazine, 10-(2-dimethylamino-l-propyl)phenothiazine, and particularly the psychotherapeutic action of chlorpromazine, 2-chloro-10-(3-dimethylamino-1 -propyl )phenothiazine, focused interest mainly on the synthesis and testing of a great number of compounds of this type. The phenothiazine drugs now play a very important part in chemotherapy. 

Antihistamines. 7(K)-7I5 dlhen/oeyciohcptuncs. 711-712. 7121 diben/ocycloheplenes. 711-712. 7l2f discovery and dcvelcpmcni of. 7(X). 

Antagonists - Recent structure-activity studies of Hj -receptor antihistamines have been concerned with stereochemical aspects, partition characteristics, pattern recognition, affinity contributions to activity and association phenomena. The subject has also been reviewed recently. Undoubtedly, the main focus of attention has been on the H2 receptor histamine antagonists. Three compounds have been widely studied, viz. burimamide (13b), metiamide (13c) and cimetidine (13d), and their pharmacological properties summarized. 3 Their discovery and development at SK F was the culmination of a research programme initiated in 1964. The search for an antagonist and some of the medicinal chemical approaches used in the structure-activity analysis have been outlined in several articles. Concurrently, other researchers had sought... 

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