H2-antagonist Activity Research Articles

Development of a new physicochemical model for brain penetration and its application to the design of centrally acting H2 receptor histamine antagonists.

A rational approach to the design of centrally acting agents is presented, based initially upon a comparison of the physicochemical properties of three typical histamine H2 receptor antagonists which do not readily cross the blood-brain barrier with those of the three brain-penetrating drugs clonidine (6), mepyramine (7) and imipramine (8). A good correlation was found between the logarithms of the equilibrium brain/blood concentration ratios in the rat and the partition parameter, delta log P, defined as log P (1-octanol/water)-log P (cyclohexane/water), which suggests that brain penetration might be improved by reducing overall hydrogen-bonding ability. This model has been employed as a guide in the design of novel brain-penetrating H2 antagonists by the systematic structural modification of representatives of different structural types of H2 antagonists. Although marked increases in brain penetration amongst congeners of cimetidine (1), ranitidine (9), and tiotidine (10) were achieved, no compound was found with an acceptable combination of H2 antagonist activity (-log KB in the guinea pig atrium greater than 7.0) and brain penetration (steady-state brain/blood concentration ratio greater than 1.0). Conversely, structural modification of N-[[(piperidinyl-methyl)phenoxy]propy]acetamide (30) led to several potent, novel compounds which readily cross the blood-brain barrier. One of these, zolantidine (SK&F 95282, 41), whose -log KB is 7.46 and steady-state brain/blood ratio is 1.4, has been identified for use in studying histaminergic H2 receptor mechanisms in brain. Comparison of delta log P values with the logarithms of the brain/blood ratios for 20 structurally diverse compounds for which data became available confirms a highly significant correlation and supports the general validity of this model.

Synthesis and histamine H2-antagonist activity of 4-quinazolinone derivatives.

With the aim of developing new atiulcer agents, a series of 4-quinazolinone derivatives was synthesized and tested for histamine H2-antagonist activity and gastric antisecretory activity. Thus, 2-alkylamino- (8a-d, 10a-s), 2-alkylthio- (15), and 2-alkyl-4-quinazolinones (18a-k) were prepared by the condensation of alkylamines with 2-chloro- or 2-methlthio-4-quinazolinones, the condensation of alkyl bromides with 2-mercapto-4-quinazolinones, and the condensation of alkylcarboxylic acids with anthranilamides, respectively.Several of the 4-quinazolinone derivatives thus synthesized showed potent H2-antagonist activity, and one of them, 2-[3-[3-(1-piperidinylmehyl)phenoxy]propylamino]-4(3H)-quinazo-linone (8d) showed the most potent antisecretory activity. The structure-activity relationships are discussed.

In Vitro Isolated Tissue Studies with Atiprosin (AY-28,228)

Using in vitro isolated tissue and binding studies we have defined a receptor activity profile for atiprosin. The most prominent action of the compound was significant alpha-adrenoceptor antagonist activity (pA2 = 8.11) that was less potent than prazosin (pA2 = 8.78) but more potent than either ketanserin (pA2 = 7.34) or indoramin (pA2 = 7.85). In addition, atiprosin was selective for alpha 1-adrenoceptors, since the compound was over 100-fold less potent as an antagonist at alpha 2-adrenoceptors (pA2 = 6.04). Atiprosin also displayed selective serotonin 5-HT2-receptor antagonist activity similar to that seen with ketanserin, but with a lesser potency (pA2 atiprosin, 6.87; ketanserin, 8.61). Although atiprosin also displayed significant histamine H1-antagonist activity (pA2 = 7.32), it was less potent as an H1-antagonist than as an alpha 1-adrenoceptor antagonist. In contrast, both indoramin and ketanserin displayed H1-antagonist activity (pA2 8.77 and 8.83, respectively) greater than their respective alpha 1-adrenoceptor antagonist activities. Atiprosin had little or no activity at either beta 1- or beta 2-adrenoceptors, muscarinic or histamine H2-receptors, nor any marked ability to produce smooth muscle relaxation either by a direct effect or via calcium entry blockade.

Effect of cetirizine, a new histamine H 1 antagonist, on airway dynamics and responsiveness to inhaled histamine in mild asthma

Cetirizine, a major human metabolite of hydroxyzine, preserves the histamine H1-antagonist activity of the parent compound but poorly penetrates the blood-brain barrier, thus minimizing sedative and anticholinergic effects. In 10 young (mean age 27.7 years) subjects with mild asthma (FEV1 greater than 70% predicted), we evaluated the bronchodilator and protective efficacy of 5, 10, and 20 mg of cetirizine against bronchospasm induced by histamine inhalation (0.03 to 20 mg/ml) in comparison with placebo and hydroxyzine, 25 mg, using a random, double-blind crossover design. The provocative concentration of histamine causing a 20% decline in FEV1 for all 10 subjects from the postdiluent control value was more than fourfold greater after each active drug than after placebo. Cetirizine, 5 to 20 mg, provided significantly greater protection against histamine-induced bronchospasm than hydroxyzine (p less than 0.001); moreover, a dose-dependent protective effect was noted with cetirizine. Significant bronchodilation was also found: at 60 minutes, FEV1 increased significantly after all active antihistamines compared to placebo and after 20 mg of cetirizine compared to hydroxyzine (p less than 0.05). FEV1 increased significantly at 120 minutes after hydroxyzine and after cetirizine in both the 20 and 10 mg doses compared to placebo (p less than 0.05). We conclude that in subjects with mild asthma, orally administered cetirizine provides significant dose-dependent protection against histamine-induced bronchoconstriction, which in the doses studied is superior to that produced by the parent compound, hydroxyzine. In addition, cetirizine in 5 to 20 mg doses causes acute bronchodilation. These results suggest a possible role of cetirizine in asthma therapy.

Pharmacology and Toxicology of Nizatidine

In well-established animal models, nizatidine is a potent, specific, and competitive orally active H2-receptor antagonist. In rat and dog models, species in which the absorption, plasma half-life and routes of metabolism are similar to that of humans, nizatidine was three- to four-fold more active than cimetidine and was of similar potency to ranitidine. On repeated daily dosing in dogs for two weeks, no tolerance was developed to the pharmacological action. Following oral dosing to dogs, nizatidine reduced gastric acid secretion for up to 8 h suggesting that this compound could be used in humans with a once or twice daily dosage regime. Apart from its H2-antagonist activity on the gastric mucosa, nizatidine produced few effects on the cardiovascular, respiratory, or central nervous system of animals. Nizatidine was rapidly and well-absorbed orally in mice, rats, and dogs, was widely distributed in tissues and the majority of the dose was excreted in the urine within 24 h. A similar absorption and excretion profile has been seen in humans. The plasma half-life in each of the animal species was between 1 and 2 h and no accumulation of nizatidine or its metabolites was seen in rats or dogs after daily oral administration for long periods. Similarities in the pharmacokinetic profile of nizatidine in the laboratory animals and humans supported the selection of the mouse, rat, and dog for acute and chronic toxicity studies. Nizatidine was well-tolerated in animals after both intravenous and oral administration and following single or repeated administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Tetrahydroisoquinolines as components of H2-antagonists. 27. H2-antihistaminics

In studies on structure-activity relationships of histamine H2-receptor antagonists, lamtidine-analogue derivatives of N-(3-hydroxyphenyl)guanidine and 5- and 7-hydroxy-tetrahydroisoquinoline were prepared and tested for their H2-antagonistic activity on the isolated guinea-pig atrium and on the histamine-stimulated acid secretion of the anaesthetized rat. A further aim of the investigations was to examine the influence of a lengthening of the side-chain as well as the substitution of the aminotriazole with other H2-antagonistic components, on the pharmacological data of the above-mentioned isoquinoline derivatives. All compounds made showed only little H2-antagonistic activity on the guinea-pig atrium. At the acid secretion a noticeable activity especially of the 7-hydroxy-tetrahydroisoquinoline isomers could be observed.

Synthesis and H2-antihistaminic effect of N,N'-bisheteroaryl N,N'-bisheteroaryl-substituted cyanoguanidines and 2-nitro-1,1-ethenediamines. 17. H2-antihistaminics

In studies on structure-activity relationships of histamine H2-receptor antagonists, cyanoguanidines and 2-nitro-1,1-ethendiamines, which contain the heterocyclic rings of ranitidine and cimetidine twofold, were prepared and tested for their H2-antihistaminic activity on the isolated guinea-pig atrium and on the histamine stimulated acid secretion of the anaesthetized rat. While the N,N'-disubstituted keten-N,N-acetales 8 and 11 possess markedly stronger H2-antagonistic activity than Ranitidine, the analogously substituted cyanoguanidines 3b and 6 proved to be as effective as the reference substance. The substances 3a and 13, with unsubstituted C-5 position of one heterocyclus, showed lower potency.

ChemInform Abstract: (IMIDAZOLYLPHENYL)FORMAMIDINES. A STRUCTURALLY NOVEL CLASS OF POTENT HISTAMINE H2 RECEPTOR ANTAGONISTS

AbstractAus den Imidazolen (I) erhält man über die Cyanamidine (II) die Amidine (III).

(Imidazolylphenyl)formamidines. A structurally novel class of potent histamine H2 receptor antagonists.

Structure-activity considerations of N alpha-guanylhistamine, the first compound found with detectable H2-antagonist activity, led to the synthesis of a series of conformationally rigid guanylhistamine analogues, namely, (imidazolylphenyl)guanidines, imidazolylbenzamidines, and (imidazolylphenyl)formamidines. It was found that in the guanidine and benzamidine classes, the meta-substituted derivatives (3, 4, 7, and 8) possessed H2-antagonist activity, whereas in the class of formamidines, only the para-substituted derivative 10 was found active. A subsequent increase in the size of the substituent at the formamidino group of 10 led to compounds (15-20) of high H2-antagonist affinity, which was related to the gastric antisecretory effect. Members of this structurally novel class of H2 antagonists were 20- to 50-fold more potent than cimetidine both "in vitro" and "in vivo". Structure-activity relationships are discussed in terms of ionization properties, partitioning behavior, conformational aspects of the selected compound 17, and of possible modes of interaction with the histamine H2 receptor. It was found that the formamidine moiety was an important structural feature and that H2-antagonist activity requires correct steric and electronic properties. Compound 17 (DA 4577), owing to its pharmacological profile and demonstrated safety in animals, was selected to be clinically investigated.

The effects of astemizole on histamine-induced weal and flare

The effect of astemizole on the weal and flare response to intradermal histamine has been studied in normal volunteers after single dosing, and in patients with urticaria and pruritus after chronic dosing with the drug. Single doses of astemizole (40 mg) in normal volunteers significantly reduced histamine weal and flare at 24 and 48 h (p less than 0.001). Before treatment, there was a significantly greater response to intradermal histamine in patients with urticaria than pruritus (p less than 0.05). Chronic dosing with astemizole produced significant reduction in histamine-induced weal and flare in both patient groups which did not show evidence of tachyphalaxis over the period of the study. The effect of astemizole on histamine-induced weal and flare was accompanied by a significant increase in the rate of weal and flare disappearance in both patients (weal p less than 0.002, flare p less than 0.05) and volunteers (weal p less than 0.02, flare p less than 0.005); but there was no change in the rate of weal formation. The effects of astemizole on weal and flare kinetics may be a function of its high level of H1 antagonist activity.

Clinical Pharmacology of H2 Receptor Antagonist.

Black and co-workers introduced the first H2 antagonist, burimamide, in 1970. Metiamide(1971) which possessed H2 antagonist activity ten times as potent as burimamide replaced it. However, metiamide was withdrawn due to severe adverse reactions such as agranulocytosis.