The histamine H2-receptor has been implicated in the autoregulation of endogenous histamine release from actively sensitized human basophils. Consequently, the activity of metiamide (SK & F 92058), a specific histamine H2-receptor antagonist, was investigated for its effect on immunologically-induced histamine release in several in vitro models of immediate hypersensitivity. Metiamide enhanced the release of histamine from passively sensitized fragmented Rhesus monkey lung and skin when these tissues were challenged in a reversed type anaphylactic reaction with antihuman IgE. The enhancing effect of metiamide on the release of 'slow reacting substance of anaphylaxis, from monkey lung was considerably less pronounced. In contrast, metiamide failed to significantly enhance the antigen-induced release of histamine from fragmented rat lung which had been passively sensitized with rat anti-ovalbumin serum.The data supports a species-specific enhancement of immunologic histamine release in vitro, perhaps by H2-receptor blockade on cells responsible for such release.

No abstract

A series of 1-(substituted phenoxy)-3-(tert-butylamino)-2-propanols in which the ring substituents were 3,4-dihydroxy (6f), 3- and 4-hydroxy (6g and 6h, respectively), 3-hydroxy-4-methylsulfonamido (6i), its 3,4-transposed isomer (6j), and 4-methylsulfonylmethyl (6k) was prepared and examined for beta-adrenergic agonist and/or antagonist properties. Two of these compounds, 6f and 6j, were potent beta-adrenoreceptor agonists in in vitro tests that measure a compound's ability to relax guinea pig tracheal smooth muscle and to increase the rate of contraction of guinea pig right atria. Several compounds had a dose-dependent effect. Although they produced potent beta-adrenergic agonist activity at low concentrations, 6g, 6h, and 6j antagonized the effects of a standard beta-adrenoreceptor agonist at higher concentrations. The methylsulfonylmethyl derivative 6k produced beta-adrenergic blocking effects as demonstrated by attenuation of isoproterenol-induced increases in the rate of contraction of an isolated rabbit heart preparation. On the basis of these pharmacological results, coupled with NMR spectral data, it appears that the previous suggestion that aryloxypropanolamines interact with beta-adrenocreceptors as a consequence of their ability to assume an orientation in which the benzene ring the ethanolamine moieties can be superimposed on those of corresponding adrenergic phenylethanolamines is invalid. An alternative "bicyclic" rigid conformation involving two intramolecular hydrogen bonds in the protonated form of the aryloxypropanolamines is suggested to account for the similar beta-adrenoreceptor activity of these compounds and related phenylethanolamines.

The m-phenolic group of catecholamine beta-adrenergic agonists may be replaced by various functionalities capable of undergoing H bonding. Considerable latitude in the nature of the OH simulating group is permissible with retention of activity; however, the most extensively studied analogs are ones in which a mobile proton is attached to an O or N atom. In a search for new selective bronchodilators a series of catecholamine analogs bearing a substituted sulfonyl or sulfonylalkyl group in the meta position (i.e., groups in which the mobile H is attached to a C atom) was examined. These compounds were studied for beta-adrenergic agonist activity in vitro by measuring their ability to relax tracheal smooth muscle and to increase the rate of spontaneously beating right atria of guinea pigs. Adrenergic activity was influenced by the nature of the alkylene bridge between the sulfonyl and aromatic groups, branching of the ethanolamine side chain, stereochemistry, and substitution of the sulfonyl and amino groups. Beta-adrenergic blockage was noted for some compounds having the sulfonyl attached directly to the ring. Greatest beta-adrenergic agonist potency and tissue selectivity was observed with a m-MeSO2CH2 substituent. One of these compounds, alpha-[[(1,1-dimethylethyl)amino]methyl]-4-hydroxy-3-[(methylsulfonyl)methyl]benzenemethanol hydrochloride (sulfonterol hydrochloride, USAN), was studied more extensively in animals and is presently being examined for bronchodilator activity in man.

No abstract