Some chemical aspects of histamine H2-receptor antagonists.

Certain chemical properties, which may determine the biological actions of the recently discovered histamine H2-receptor antagonists burimamide and metiamide, are identified, partly by considering the derivation of these antagonists. Examples are given of attempts to design antagonists using histamine as starting point. A partial agonist was eventually obtained through modifying the side chain of histamine but retaining the imidazole ring. Further developments led to the synthesis of uncharged thioureido analogues and to the discovery of the antagonist, burimamide. Consideration of the relative concentration of imidazole tautomers led to the replacement of a methylene group (-CH2-) with an isosteric thioether (-S-) link in the side chain, and incorporation of a methyl group in the imidazole ring; these changes afforded metiamide, an orally active antagonist. These developments emphasize that the imidazole ring appears to have a special importance at H2 receptors. Burimamide and metiamide are hydrophilic molecules that resemble histamine in having an imidazole ring but differ in the side chain which, though polar, is uncharged. By contrast, the H1-receptor antihistaminic drugs are lipophilic molecules; their resemblance to histamine is in having a positively charged ammonium side chain. These substantial chemical differences between the respective antagonists probably determine their selectivity in distinguishing between the two types of histamine receptor. Furthermore, the very low lipophilicities of these H2-receptor antagonists probably account for the lack of central nervous system and local anesthetic effects normally associated with the use of antihistaminic drugs.     

Localization of histamine and histamine H2-receptor antagonists in the gastric mucosa.

Synopsis Histamine stimulates acid secretion by the parietal cell and this secretion is inhibited by the histamine H₂-receptor antagonists. Whole body autoradiography showed that radioactivity from¹⁴C-histamine was localized in the artery walls of the stomach and in the muscularis mucosae, but that the level in the fundic mucosa was the same as the blood.When the H₂-receptor antagonists burimamide, metiamide and cimetidine were labelled with³⁵S,¹⁴C or³H and dosed to rats, whole body autoradiography showed that the stomach was predominantly labelled in the glandular mucosa from 5 to 120 min after administration. Microautoradiography in the rat and dog after intravenous injection of [³H] metiamide or [³H] cimetidine demonstrated an uptake of tritium in the parietal cell cytoplasm that was 3- to 4-times greater than that found in adjacent peptic cells or areas of muscularis mucosa. The preferential labelling persisted at a low level up to 6 h after injection in the rat. The localization of radioactivity from the H₂-antagonists in the parietal cell cytoplasm correlates well with their pharmacological activity in preventing acid secretion from this cell.     

A Quantitative study of histamine H2-receptor bockade by burimamide in isolated artica.

The onset of burimamide inhibition of histamine stimulation of rabbit atria is rapid, and a near steady-state blockade occurs at approximately 15 min ( larger than or equal to 90% complete). The blockade is reversible but requires several washings suggesting the disassociation is slow. The administration of histamine may accelerate the decay of the burimamide effect. Reciprocal plots (rate response versus histamine concentration) of dose-response curves are linear for both rabbit and guinea pig atria. In the presence of low concentrations of burimamide; (2.4 times 10-5 M), the displacement of curves suggests a competitive type of inhibition both for rabbit and guinea guinea pig atria. The apparent association constants calculated from these curves are: K1 (rabbit) 3.7 times 10-6M and K-1 (guinea pig) 6.7 times 10-6M. These results for guinea pig atria are in satisfactory agreement with the value obtained in another laboratory (2). At higher concentrations of burimamide, inhibition curves showed distinct evidence of departure from competitive character for both guinea pig and rabbit atria.     

In vitro and in vivo comparisons of antiandrogenic potencies of two histamine H2-receptor antagonists, cimetidine and etintidine--HCl

The antiandrogenic potency of cimetidine was compared to that of a new histamine H2-receptor antagonist, etintidine-HCl (ORF 16753-02). Although both compounds displaced [3H]dihydrotestosterone from androgen receptors in vitro and inhibited androgen-stimulated growth of the accessory sex organs of male rats in vivo, etintidine-HCl was significantly less antiandrogenic than cimetidine in the analysis of androgen receptor binding and in the inhibition of seminal vesicle weights. Because etintidine-HCl has been shown previously to have more potent gastric antisecretory activity than cimetidine, its lower antiandrogenic activity suggests that etintidine-HCl has a much wider therapeutic ratio and that its use clinically will result in fewer antiandrogenic side effects.     

On the specificity of histamine H2-receptor antagonists in the rat cerebral cortex.

The effects of iontophoretically applied histamine H2-receptor antagonists and their antagonism of various amines, acetylcholine (ACh), and adenosine 5'-monophosphate (5'-AMP) were studied on spontaneously active rat cerebral cortical neurons. Metiamide selectively blocked the depressant actions of histamine. Burimamide, in amounts necessary for histamine antagonism, also antagonized the depressant effects of noradrenaline, dopamine, and 5-hydroxytryptamine. Neither antagonist affected 5'-AMP-induced depressions, but both reduced or blocked the excitatory actions of ACh. It is concluded that metiamide may be useful as a reliable antagonist of H2 receptors on cerebral cortical neurons.     

Synthesis and SAR studies of benzimidazolone derivatives as histamine H3-receptor antagonists

A novel series of benzimidazolone-containing histamine H₃-receptor antagonists were prepared and their structure–activity relationship was explored. These benzimidazolone analogs demonstrate potent H₃-receptor binding affinities, no P450 enzyme inhibition, and strong H₃ functional activity. Compound 1o exhibits the best overall profile with H₃K_i = 0.95 nM and rat AUC = 12.9 μM h.     

Analogues and derivatives of ciproxifan, a novel prototype for generating potent histamine H3-receptor antagonists

Novel derivatives of the highly potent and selective histamine H3-receptor antagonist ciproxifan (3) with different chain lengths as well as with structural variants of the cyclopropyl ketone moiety have been prepared and screened for their antagonist H3-receptor potencies in vitro and in vivo. Some derivatives (2, 6-8, 12) containing other functionalities were effective in vitro in the same (sub)nanomolar concentration range and in vivo in a remarkably low oral dose.     

Effects of histamine and H1 and H2-receptor antagonists on wet-dog-shake episodes in rats induced with tranylcypromine and 5-methoxytryptamine

Intraperitoneally administered tranylcypromine and 5-methoxytryptamine induced in rats the so called wet-dogs-shake behaviour. Histamine injected intraventricularly had no effect on the number or episodes of this behaviour during the first 40 minutes of observation. On the other hand, dimaprit in doses of 5 micrograms/rat injected also intraventricularly increased the number of these episodes. Thenalidine and antazoline--antagonists of the H1-receptor, and cimetidine and ranitidine--antagonists of the H2-receptor, decreased the number of these episodes proportionally to the injected dose. Similar effects were obtained after cimetidine injection into the lateral ventricle. In the light of these observations it may be supposed that these antihistaminic agents exert an inhibitory effect not only on the histaminergic system but decrease indirectly also the activity of the serotoninergic system.     

Influence of histamine and H1-receptor antagonists on ejaculated human spermatozoa: role of intrasperm Ca2+

Histamine reduced sperm viability in a dose- and time-dependent manner, accompanied by rise in intrasperm Ca2+. Further, 2',4'-dichlorobenzamil hydrochloride (DBZ), a Na+-Ca2+ exchange inhibitor, known to elevate intrasperm Ca2+, potentiated both, elevation of intrasperm Ca2+ and spermicidal action of histamine. Pretreatment of sperm with very low doses of H1-receptor antagonists (chlorpheniramine, promethazine or diphenhydramine) prevented the histamine-induced elevation of intrasperm Ca2+ as well as its spermicidal action. However, pretreatment with famotidine, a H2-receptor antagonist did not produce such a protective action. The results strongly suggest that histamine elicits its spermicidal action via H1-receptors present on sperm cells.     

2-Aryloxymethylmorpholine histamine H(3) antagonists

The synthesis and biological activity of a new series of 2-aryloxymethylmorpholine histamine H(3) antagonists is described. The new compounds are high affinity histamine H(3) ligands that penetrate the CNS and occupy the histamine H(3) receptor in rat brain.     

Effect of H2-receptor antagonists, cimetidine and ranitidine on reproductive functions in male mice.

Na+,K(+)-ATPase and Ca(2+)-ATPase in testis were inhibited with an oral administration of cimetidine and ranitidine. Cimetidine at dose level of 100 and 30 mg while ranitidine at 70 and 10 mg per kg body wt inhibited the enzyme activities, 24 hr after single administration or daily administration for 15-days. Mg(2+)-ATPase activity was increased with cimetidine while ranitidine inhibited the enzyme. Michaelis-Menten kinetic characteristics revealed mixed type of inhibition for Na+,K(+)-ATPase with cimetidine, whereas it was noncompetitive for Ca(2+)-ATPase with cimetidine as well as ranitidine administration. Inhibition of Na+,K(+)-ATPase with ranitidine was also of noncompetitive type. Mg(2+)-ATPase behaved differently with administration of ranitidine at both the time points used i.e. noncompetitive type of inhibition after 24 hr and mixed type after 15-days. Histologically, signs of degeneration of testicular elements appeared after administration of cimetidine with a significant decrease in tubular diameter and germinal epithelial cell height. Ranitidine administration did not produce any change in the seminiferous tubules of testis. Scanning electron microscopy of spermatozoa from cimetidine-treated mice exhibited distinct departure from the normal morphology such as, (i) breaks at various places along distal portion of the tail, (ii) roughening, wrinkling and disorganization of plasma membrane of the head region, (iii) decapitation of the head and (iv) changes in shape of cytoplasmic droplet. Ranitidine administration showed normal morphology of the spermatozoa.     

Predictors of torsades de pointes in rabbit ventricles perfused with sedating and nonsedating histamine H1-receptor antagonists

Several nonsedating histamine H1-receptor antagonists are associated with torsades de pointes ventricular tachycardia. The objectives of this study were to: (i) compare electrocardiographic, monophasic action potential, and arrhythmogenic effects of sedating and nonsedating H1-receptor antagonists, and (ii) identify correlates of drug-induced torsades de pointes in an isolated ventricle model. Isolated, electrically paced (1-3 Hz) rabbit ventricles were Langendorff-perfused with either drug-free Tyrode's solution or one of the following: (i) the sedating H1-receptor antagonist hydroxyzine (0.1-30 microM), (ii) cetirizine, a nonsedating metabolite of hydroxyzine (1-300 microM), and (iii) the nonsedating, putatively arrhythmogenic H1-receptor antagonist astemizole (0.1-30 microM). Volume conducted electrocardiographic signals and monophasic action potentials from the periapical left ventricular endocardium and epicardium were recorded. There were no apparent changes in control (n = 15) or hydroxyzine-perfused (n = 7) hearts. Cetirizine (n = 13) produced a mild biphasic electrocardiographic QT interval prolongation and was associated with early afterdepolarizations, but not with torsades de pointes. Astemizole (n = 11) lengthened QT intervals, and at high concentration (30 microM) induced torsades de pointes in 10 of 11 hearts (P < 0.001 vs. all other groups). These findings are consistent with previously reported repolarizing current inhibition by cetirizine, but may additionally indicate "compensatory" inhibition of inward currents at higher concentrations. By contrast, astemizole-induced changes are consistent with unopposed repolarizing current inhibition.     

Bicarbonate stimulatory action of nizatidine, a histamine H(2)-receptor antagonist, in rat duodenums.

Nizatidine, a histamine H(2)-antagonist, is known to inhibit acetylcholinesterase (AChE) activity and is used clinically as a gastroprokinetic agent as well as the anti-ulcer agent. We examined whether or not nizatidine stimulates duodenal HCO(3)(-) secretion in rats through vagal-cholinergic mechanisms by inhibiting AChE activity. Under pentobarbital anesthesia, a proximal duodenal loop was perfused with saline, and the HCO(3)(-) secretion was measured at pH 7.0 using a pH-stat method and by adding 10 mM HCl. Nizatidine, neostigmine, carbachol, famotidine or ranitidine was administered i.v. as a single injection. Intravenous administration of nizatidine (3-30 mg/kg) dose-dependently increased the HCO(3)(-) secretion, and the effect at 10 mg/kg was equivalent to that obtained by carbachol at 0.01 mg/kg. The HCO(3)(-) stimulatory action of nizatidine was observed at the doses that inhibited the histamine-induced acid secretion and enhanced gastric motility. This effect was mimicked by neostigmine (0.03 mg/kg) and significantly attenuated by bilateral vagotomy and pretreatment with atropine but not indomethacin. The IC(50) of nizatidine for AChE of rat erythrocytes was 1.4 x 10(-6) M, about 12 times higher than that of neostigmine. Ranitidine showed the anti-AchE activity and increased duodenal HCO(3)(-) secretion, similar to nizatidine, whereas famotidine had any influence on neither AChE activity nor the HCO(3)(-) secretion. On the other hand, duodenal damage induced by acid perfusion (100 mM HCl for 4 h) in the presence of indomethacin was significantly prevented by nizatidine and neostigmine, at the doses that increased the HCO(3)(-) secretion. These results suggest that nizatidine increases HCO(3)(-) secretion in the rat duodenum, mediated by vagal-cholinergic mechanism, the action being associated with the anti-AChE activity of this agent.     

H2 histaminic receptors in rat cerebral cortex. 2. Inhibition of [3H]histamine by H2 antagonists

Sites labeled by [3H]histamine in homogenates of rat cerebral cortex reveal a pharmacological specificity typical of H2 receptors. Fourteen H2 antagonists inhibit the specific binding of the radioligand to the same level; Hill coefficients are near or equal to one for five compounds and markedly lower for nine. The binding patterns of individual antagonists (A) are well described by the empirical expression Y = F1K1/(K1 + [A]) + F2K2/(K2 + [A]), in which F1 and F2 sum to 1; F2 is 0 for those drugs that reveal a Hill coefficient of 1. Concentrations of A that reduce specific binding by 50% (IC50) correlate well (r = 0.991; P less than 0.00001) and show good numerical agreement with potencies reported for inhibition of the response to histamine in H2-mediated systems. The correlation is poorer when IC50 is replaced by either K1 (r = 0.973) or K2 (r = 0.921) for those antagonists that reveal both; the antihistaminic activity of the drug thus appears not to be associated preferentially with one or other class of sites. Since F2 varies from 0.16 to 0.60 among those antagonists that discern heterogeneity, the antagonist appears to determine the distribution of sites between the two classes. Moreover, a correlation among antagonists between values of K1 and K2 (r = 0.975; P = 0.00001) suggests that the apparent heterogeneity reflects different conformers within an otherwise homogeneous population. H2 antagonists appear to be noncompetitive with respect to each other and to the radioligand: one antagonist has relatively little effect on the values of K1, K2, and F2 revealed by another; also, estimates of K1 and K2 are independent of the concentration of [3H]histamine between 1.3 and 10 nM, although the radioligand exhibits an apparent dissociation constant of 3.9 nM [Steinberg, G. H., Eppel, J. G., Kandel, M., Kandel, S. I., & Wells, J. W. (1985) Biochemistry (preceding paper in this issue)].     

Indole- and benzothiophene-based histamine H3 antagonists

Previous research on histamine H₃ antagonists has led to the development of a pharmacophore model consisting of a central phenyl core flanked by two alkylamine groups. Recent investigation of the replacement of the central phenyl core with heteroaromatic fragments resulted in the preparation of novel 3,5-, 3,6- and 3,7-substituted indole and 3,5-substituted benzothiophene analogs that demonstrate good to excellent hH₃ affinities. Select analogs were profiled in a rat pharmacokinetic model.     

Modification by histamine H2-receptor blockade of acid secretion stimulated by histamine, pentagastrin and methacholine in the isolated whole mouse stomach.

The direct influences of the blockade of the gastric histamine H2-receptors on the secretory actions induced by histamine, pentagastrin and methacholine, have been studied on the isolated perfused whole mouse stomach. According to the results cimetidine did not modify the spontaneous basal acid secretion. The interactions of cimetidine with the secretagogues were of a competitive nature with histamine and non-competitive with pentagastrin, while no modification of methacholine stimulated acid secretion.     

Characterization of histamine H1-receptor on rat hepatocytes

The binding sites for [3H]pyrilamine in isolated rat hepatocytes were characterized. Scatchard analysis revealed two kinds of binding sites in hepatocytes, a high-affinity site and a low-affinity one. The rates of binding of the radioligand with the high-affinity binding site and its dissociation were rapid. The specificity of the sites for various histamine antagonists indicated that the high-affinity [3H]pyrilamine binding site is representative of the histamine H1 receptor. Treatment of hepatocytes with protease or phospholipase A2 significantly decreased the maximum binding capacity of the high-affinity site without affecting its dissociation constant, suggesting that the binding site is proteinaceous and is sensitive to a change in the lipid moiety of the membrane. Hepatocytic cyclic AMP and cyclic GMP were not significantly modulated by incubating hepatocytes with histamine. Thus, the action of histamine on hepatocytes might not be mediated by the cyclic nucleotides.