Histamine receptor Subject

Hj, Hj, and Hj receptors are present in the CNS. Tricyclic antidepressant drugs seem to interact with histamine receptors in the CNS. Histamine receptor subtypes in the CNS and the central neurotransmitter role of histamine have been the subject of many recent investigations. Currently there are three central histamine receptors ... 

Adverse effects Hi receptor blockers have a low specificity, that is, they interact not only with histamine receptors but also with muscarinic cholinergic receptors, a-adrenergic receptors, and serotonin receptors (see Figure 40.6). The extent of interaction with these receptors and, as a result, the nature of the side effects, vary with the structure of the drug. Some side effects may be undesirable, and others may have therapeutic value. Furthermore, the incidence and severity of adverse reactions varies between individual subjects. 

Histamine receptors were reviewed in 1973 before the advent of the H2 antagonists later developments are described in reference 4, and the subject was mentioned briefly in these reports in 1975 and 1977. The classification and distribution of histamine receptors has been discussed by Black and reviewed by Chand and Eyre. The Physiological Society of Philadelphia held a symposium on histamine receptors in 1977, the proceedings of which are in press. A symposium was held in 1978 at the Vlth International Conference on Medicinal Chemistry, Brighton, England (proceedings to be published). In addition, there have been several symposia on H2-receptor histamine antagonists, mainly concerned with clinical aspects. 

Multiple stimuli for the release of gastric acid exist, so blockade of the histamine receptor only decreases secretion to the extent that other stimuli are present or absent. Proton-pump inhibitors act at the last step of gastric acid synthesis and thus are not subject to the effects of other mediators. 

White JP, Mills J, Eiser NM Comparison of the effects of histamine H,- and Hj-receptor agonists on large and small airways in normal and asthmatic subjects. Br J Dis Chest 1987 81 155-169. 

The selective C-labeled antagonist of the histamine 1 (Hi) receptor [ C]doxe-pin has been used in a study of 11 healthy subjects and 10 AD patients with PET. The binding potential of Hi receptors showed a significant decrease especially in the frontal and temporal areas of the brain in patients with AD. In addition, the... 

Another proposed mechanism is inhibition of cell-surface receptors for adenosine. These receptors modulate adenylyl cyclase activity, and adenosine has been shown to provoke contraction of isolated airway smooth muscle and histamine release from airway mast cells. It has been shown, however, that xanthine derivatives devoid of adenosine antagonism (eg, enprofylline) may be potent in inhibiting bronchoconstriction in asthmatic subjects. 

The Hi Receptor and its Ligands. The H receptor mediates effects, through an increase in cyclic adenosine monophosphate (cAMP). such as gastric acid secretion relaxation of airway smooth muscle and of pulmonary vessels increased lower airway mucus secretion esophageal contraclion inhibition of basophil, but not mas cell histamine release inhibition of neutrophil activation and induction or suppressor T cells. There is no evidence that the H- receptor causes significant modulation of lung function in the healthy human subject or in the asthmatic. 

The antidepressant effect of thymoleptics manifests after a prolonged latency usually 1-3 weeks pass before subjective or objective improvement becomes noticeable (A). In contrast, somatic effects are immediately evident specifically, the interference with neuronal transmitter/modulator systems (norepinephrine, serotonin, acetylcholine, histamine, dopamine). Reuptake of released serotonin, norepinephrine, or both is impaired (—< elevated concentration in synaptic cleft) and/or receptors are blocked (example in A). These effects are demonstrable in animal studies and are the cause of acute adverse effects. 

Early study of bronchoconstricitive mechanisms of sulfur dioxide with ventilated, tracheostomized cats indicated that pulmonary resistance increased during the first breath but reversed rapidly (Nadel et al. 1965). Intravenous injection of atropine (a parasympathetic receptor blocker) or cooling of the cervical vagosympathetic nerves abolishes bronchoconstriction rewarming the nerve reestablishes the response. The rapidity of the response and its reversal emphasize the parasympathetically mediated tonal change in smooth muscle. Studies with human subjects have confirmed the predominance of parasympathetic mediation, but histamine from inflammatory cells could play a secondary role in the bronchoconstrictive responses of people with asthma (Sheppard et al. 1981). 

Episodes of airway obstruction or bronchoconstriction may be induced in asthmatics by exposure to stimuli to which they are sensitized, such as inhalation of a specific pollen or house dust mite, or exposure to an occupational stimulus, e.g., red cedar dust [47]. Binding of antigen (e.g., pollen) to specific receptors (antibodies) on the surface of an inflammatory cell (e.g., mast cell) results in the elaboration of prestored mediators, such as histamine, and in the synthesis of newly formed mediators, such as arachidonic acid metabolites (e.g., prostaglandins and leukotrienes). Cellular sources of the various mediators are shown in Table 3. Cytokines and chemokines are proteins that participate in pulmonary immune and inflammatory responses. While important, these have not been subjected to discussion in this chapter because these fields are changing very... 

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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