Synthese und kombinierte H1-/H2-antagonistische Aktivität von Mepyramin-, Pheniramin- und Cyclizin-Derivaten mit Cyanoguanidin-, Harnstoff- und Nitroethendiamin-Partialstrukturen

Synthesis and Combined Histamine H₁ - and H₂-Receptor Antagonist Activity of Mepyramine, Pheniramine, and Cyclizine Derivatives with Cyanoguanidine, Urea, and Nitroethenediamine Groups Compounds with combined histamine H₁- and H₂-receptor antagonist activity were synthesized by connecting H₁ and H₂-receptor substructures via cyanoguanidine, urea, or nitroethenediamine moieties. Loss of the strongly basic side-chain nitrogen results in a decrease of H₁-receptor activity compared to single reference compounds. At the guinea-pig right atrium (H₂-receptor model) compounds with mepyramine or cyclizine structure are also less active than the single references tiotidine, ranitidine, or lamtidine. Nevertheless substances with a pheniramine like partial structure proved to be potent histamine H₂-receptor antagonists at the atrium model (about 27 times more active than cimetidine).     

Relaxant response of goat trachea to 5-hydroxytryptamine mediated by D-tryptamine receptors

1 Goat isolated trachea contracted in response to carbachol, histamine and 2-pyridylethylamine (an H₁-receptor agonist) and relaxed after application of isoprenaline. 5-hydroxytryptamine (5-HT) and phenylephrine.

2 Mepyramine, a selective H₁-receptor antagonist, blocked histamine- and 2-pyridylethylamine-induced contractions. In high doses it also exhibited some nonspecific antagonism to carbachol. After H₁-receptor blockade, 4-methylhistamine and dimaprit (specific H₂-agonists) relaxed the carbachol-contracted trachea.

3 Propranolol, a β-adrenoceptor blocker, antagonized relaxation in response to isoprenaline and phenylephrine. In high doses, it produced a reversal of the phenylephrine response.

4 Indomethacin enhanced contractions in response to carbachol and histamine.

5 Relaxation to 5-HT was not affected by propranolol, indomethacin, metiamide or cimetidine (H₂-blockers). These findings appear to exclude the involvement of adrenergic, prostaglandinergic and H₂-histaminergic mechanisms in the mediation of this response.

6 Atropine potentiated 5-HT-induced relaxations. This suggests the participation of a `masked' excitatory cholinergic mechanism.

7 Methysergide, dibenamine and dibenzyline selectively antagonized or reversed 5-HT-induced relaxation. Dibenamine and dibenzyline enhanced relaxations to isoprenaline.

8 This investigation showed (i) a relaxant response of goat trachea to 5-HT, mediated via D-muscular tryptamine receptors; (ii) a small population of excitatory M-neuronal tryptamine and α-adrenoceptors; and (iii) predominance of H₁-histamine receptors in the goat trachea.

     

Dual histamine receptor mechanism in guinea-pig lung.

Isolated guinea-pig lung parenchymal strips (GPLS) relaxed in response to the selective histamine H2-receptor agonists, dimaprit and 4-methylhistamine (4-MeH), and to low doses of histamine (10(-9) to 10(-7) mol/l) and contracted in response to several spasmogens. The order of the relative activity of the spasmogens was 2-methylhistamine (2-MeH) greater than histamine greater than carbachol greater than 2-pyridylethylamine (2-PE). Dimaprit and 4-MeH also relaxed GPLS which were contracted by 2-MeH, 2-PE or carbachol. Metiamide (a selective H2-antagonist: 5 x 10(-5) mol/l inhibited or reversed relaxations to histamine, dimaprit and 4-MeH, and significantly enhanced contractile responses to histamine without altering responses to carbachol. Mepyramine (a selective H1-receptor antagonist: 10(-8) to 10(-6) mol/l antagonized histamine-induced contractions. This investigation shows: (1) histamine is more active than carbachol in GPLS and (2) the occurrence of histamine H1-receptors mediating contraction and H2-receptors mediating relaxation in guinea-pig lung.     

Azines and Diazines as Potential Histamine H3-Receptor Antagonists

In search of structure-activity relationships among histamine H₃-receptor antagonists the imidazole ring of known H₃-receptor antagonists was replaced by different heteroaromatic ring systems. Thus, azines and diazines with ether ( 6 – 13 ) and carbamate ( 15 – 24 ) moieties as functional groups were synthesized. The obtained compounds did not show significant H₃-receptor antagonist activity in vitro (rat brain cortex) or in vivo (mice brain). The new compounds were also screened for H₁-receptor antagonist activity on the isolated guinea-pig ileum and for H₂-receptor antagonist activity on the isolated spontaneously beating guinea-pig right atrium. The substances showed only weak antagonistic activity at both histamine receptors, H₁ and H₂.     

Pyrazoles as Potential Histamine H3-Receptor Antagonists

In search of structure-activity relationships among histamine H₃-receptor antagonists, the imidazole ring of known H₃-receptor antagonists was replaced by different heteroaromatic ring systems. Thus, pyrazoles with ether ( 4,5 ) and carbamate ( 6,7 ) moieties as functional groups were synthesized. Reaction of the hydrochloride of 4-(3-hydroxypropyl)pyrazole ( 1 ) with phenyl or benzyl isocyanates mainly gave the carbamates 6 and 7 , whereas a similar reaction with 1 as the free base furnished the N-carbamoylpyrazoles 8 and 9 . The bifunctional pyrazoles 10 and 11 were formed as by-products. The compounds obtained did not show significant H₃-receptor antagonist activity in vitro (rat brain cortex) or in vivo (mouse brain). These results demonstrate the importance of the imidazole moiety for H₃-receptor antagonists. The new compounds were also screened for H₁-receptor antagonist activity on the isolated guinea-pig ileum and for H₂-receptor antagonist activity on the isolated spontaneously beating guinea-pig right atrium. The substances showed only weak antagonistic activity at both histamine receptors H₁ and H₂.     

Characterization of H2-receptor mediated relaxation in rabbit aortic strips

Rabbit aortic strips contracted with either KC1 (60 mM), phenylephrine (10^?5 M) or angiotensin-II (10^?7 M) were exposed to cumulative concentrations of the H₂-receptor agonists impromidine, histamine, 4-methyl histamine and dimaprit in the presence of the H₁-receptor antagonist, pyrilamine (10^?6 M). All of the H₂-receptor agonists produced a similar degree of relaxation in strips contracted with phenylephrine. The order of potency was impromidine>histamine>4-methyl histamine?dimaprit. All of the H₂-receptor agonists except 4-methyl histamine were able to produce significant degrees of relaxation in aortic strips contracted with angiotensin-II. In contrast, none of the H₂-receptor agonists, in doses which relaxed phenylephrine and angiotensin-II contracted muscles, we able to relax aortic strips contracted by KCl.When the relaxant ability of the H₂-receptor agonist, impromidine, was compared to that of D-600, isoproterenol and adenosine, it was found to produce relaxation similar to that characterized by isoproterenol. Impromidine, like isoproterenol, more readily relaxed aortic strips contracted by either phenylephrine or angiotensin-II.     

Human gastric mucosal adenylate cyclase: Activation by histamine-H2-receptor stimulation and inhibition by cimetidine in vitro and in peptic ulcer patients

Summary Biopsy specimens of human fundic mucosa from 96 subjects were assayed for adenylate cyclase activity to characterize specificity of the histamine receptor with selective agonists and antagonists in vitro, and to study the effect of cimetidine therapy. Histamine and the selective histamine H₂-receptor agonist dimaprit were almost equally potent throughout the concentration-response curve (10^–7–10^–3 mol/l); maximal stimulation was obtained with concentrations of 10^–4–10^–3 mol/l, and half maximal stimulation with about 10^–5 mol/l. The selective H₁-receptor agonist PEA 10^–5 and 10^–3 mol/l failed to stimulate adenylate cyclase. Mepyramine 10^–6 mol/l, a selective H₁-receptor antagonist, and cimetidine 10^–6 mol/l, a selective H₂-receptor antagonist, did not affect basal adenylate cyclase activity. Histamine-stimulated adenylate cyclase was inhibited in a concentration dependent manner by cimetidine 10^–7 and 10^–5 mol/l, but not by the same concentrations of mepyramine. Almost identical basal adenylate cyclase activities of about 150 pmol cAMP/mg protein/20 min were found in gastric mucosal biopsies from controls and from peptic ulcer patients, whether or not treated with cimetidine. Histamine 10^–5 mol/l doubled adenylate cyclase activity in the controls and the untreated ulcer group, but was completely ineffective in specimens from the cimetidine-treated peptic ulcer patients. The data underline the concept that the effects of histamine on acid secretion and on adenylate cyclase activity are linked together and that the therapeutic effect of cimetidine in ulcer treatment is related to histamine H₂-receptor blockade followed by inhibition of adenylate cyclase.     

Pharmacology of Schultz-Dale reaction in canine lung strip in vitro: possible model for allergic asthma

1 Isolated lung parenchymal strips of the dog contracted in response to histamine > carbachol > prostaglandin F_2α (PGF_2α) > bradykinin (Bk) > 5-hydroxytryptamine (5-HT). The order of the relative activity of these agents on the tracheobronchial smooth muscles (TBSM) was carbachol > 5-HT > histamine; PGF_2α and Bk were inactive. Thus there are marked differences in the responsiveness of the smooth muscle of central (trachea and bronchus) and peripheral (lung strip) airways to autonomic and autacoid agents.

2 Lung strips and TBSM partially contracted by carbachol, histamine or horse plasma, were relaxed by isoprenaline, PGE₁ and PGE₂.

3 Lung strips from dogs sensitized to horse-plasma contracted in response to antigen (Schultz-Dale anaphylactic reaction). Tachyphylaxis or desensitization to subsequent antigen challenge was invariably observed; it was followed after 1 to 2 h of rest by partial recovery of the anaphylactic response.

4 Mepyramine selectively antagonized responses to histamine without altering responses to carbachol and antigen.

5 Metiamide, an H₂-receptor antagonist, did not influence responses to histamine, carbachol or horse plasma.

6 Indomethacin was found to be ineffective as an inhibitor of the Schultz-Dale anaphylactic reaction.

7 The results showed the presence of H₁-histamine receptors mediating constriction in the peripheral airways of the dog. Histamine and PGF_2α appear to have no important role in the anaphylactic reaction in this tissue. The involvement of slow reacting substance of anaphylaxis (SRS-A) and endoperoxides (thromboxanes) in allergic reactions of canine lung is strongly suggested.

     

A new class of nitric oxide-releasing derivatives of cetirizine; pharmacological profile in vascular and airway smooth muscle preparations

BACKGROUND AND PURPOSE: The pharmacological properties of compounds NCX 1512 and NCX 1514, synthesized by linking the histamine H1-receptor antagonist cetirizine to NO-releasing spacer groups, are reported. The aim was to establish if the compounds retained the antihistamine action of the parent compound, to assess their efficacy as NO donors and to test if they had broader antiallergic activity than cetirizine in the lung. EXPERIMENTAL APPROACH: Antihistamine activity of NCX 1512 and NCX 1514 was investigated in vitro in the guinea pig ileum, in tracheal rings (GPTR) and lung parenchymal strips (GPLP) of the guinea-pig. The NO-releasing capacity was investigated in vascular preparations; the isolated rabbit and guinea-pig aorta and guinea-pig pulmonary artery. Kinetics of NO release were assessed in a rat whole blood assay. KEY RESULTS: Both NCX 1512 and NCX 1514 retained activity as H1-receptor antagonists in the guinea pig ileum and airway preparations. The NO-releasing NCX compounds relaxed the rabbit aorta, an action prevented by the guanylyl cyclase inhibitor ODQ (10 microM). NCX 1512 and NCX 1514 did not relax the antigen (ovalbumin) pre-contracted GPTR, whereas the NO donors NCX 2057 and DEA-NONOate relaxed guinea-pig pre-contracted vascular and tracheal preparations. Cetirizine (1-100 microM) and NCX 1512 (1-100 microM) reduced the cumulative (0.01-100 microg ml(-1)) ovalbumin-induced constriction in GPTR, but had no significant effect in GPLP. CONCLUSIONS AND IMPLICATIONS :NCX 1512 and NCX 1514 act as antihistamines and NO donors. However, there was no improved effect compared to cetirizine on antigen-induced constriction of the central and peripheral lung.     

Synthesis and Pharmacology of Combined Histamine H1-/H2-Receptor Antagonists Containing Diphenhydramine and Cyproheptadine Derivatives

The classical histamine H₁-receptor antagonists diphenhydramine ( 3a ) and cyproheptadine ( 9 ) and their derivatives ( 3b—d, 10 ) were connected with a 2-guanidinothiazole containing structure ( 28 ) derived from the H₂-receptor antagonist tiotidine in order to obtain combined H₁-/H₂-receptor antagonists. The two moieties were not directly linked together, but were separated by a polymethylene spacer and a polar group (nitroethenediamine or urea). Thus 12 compounds were obtained that proved in vitro to possess high H₁- and H₂-receptor antagonist activity at the isolated guinea-pig ileum (H₁) and the isolated guinea-pig right atrium (H₂), respectively. The incorporation of the diphenhydramine as well as the cyproheptadine component provides high affinity to H₁-receptors. The tricyclic cyproheptadine and its 10,11-dihydro derivative ( 30–32, 34 ), however, cause a decrease of H₂-receptor antagonist potency compared to the diphenhydramines ( 29a—d, 33a—d ). Using nitroethenediamine as the polar group is apparently more favourable to H₁- and H₂-receptor affinity as the urea function. All compounds elicit a dual mode of competitive and noncompetitive antagonism. Among the novel compounds the nitroethenediamines with 4-fluoro- or 4-methyl-substituted diphenhydramine as H₁-receptor antagonist moiety ( 29c, d ) display the most potent H₁- and H₂-receptor antagonist effects. The presented concept is a very promising way to combine H₁- and H₂-receptor antagonist properties in one molecule.     

Actions of betahistine at histamine receptors in the brain

The actions of betahistine (N alpha-methyl-2-pyridylethylamine) on brain histamine receptors were investigated in a series of biological models. [3H]Mepyramine binding to H1-receptors in membranes from guinea-pig cerebellum was inhibited by betahistine with a Ki value of 31 microM. The binding of [3H]mepyramine in brain of the living mouse was inhibited by betahistine in high dosages (150-300 mg/kg). In slices from mouse cerebral cortex, betahistine induced [3H]glycogen hydrolysis in a concentration-dependent manner with an EC50 value of 9.0 microM with a maximal effect 57% that of histamine. Mepyramine and triprolidine, two H1-receptor antagonists, inhibited the betahistine-induced glycogenolysis with Ki values of 28 nM and 7 nM respectively. In slices from guinea-pig hippocampus, betahistine stimulated the accumulation of cyclic AMP in the presence of 5 microM impromidine, a H2-receptor agonist. The maximal effect represented 22% of that elicited by histamine at the H1-receptor and the EC50 value was 32.4 microM. Mepyramine at 0.1 microM partially blocked the response to betahistine. Together these various observations indicate that betahistine is a partial agonist at cerebral H1-receptors. Finally, betahistine was not an agonist at histamine H3-autoreceptors but was a rather potent antagonist of the inhibitory effect of exogenous histamine on [3H]histamine release elicited by K+ depolarisation in slices from rat cerebral cortex (Ki = 6.9 microM).     

Differentiation of the roles of histamine H1- and H2-receptors in the mediation of the effects of histamine in the isolated working heart of the guinea-pig.

1 Differentiation of the roles of histamine H1- and H2-receptors in the mediation of the effects of histamine on the isolated working heart of the guinea-pig was achieved through the use of histamine and selective histamine receptor agonists and antagonists. 2 Histamine over the dose range 10(-9) mol to 10(-6) mol produced dose-related increases in sinus rate, left intraventricular pressure (LVP)max, LVdP/dtmax, coronary flow, aortic flow, total cardiac output and external pressure-volume work. 3 Dimaprit, a selective histamine H2-receptor agonist, produced very similar responses to histamine. 4 2-Pyridylethylamine, a selective histamine H1-receptor agonist, had little effect on cardiac function unless large doses were administered. Such doses produced increases in all measured parameters. 5 Cimetidine, a selective histamine H2-receptor antagonist, antagonized the effects of histamine and dimaprit and some but not all effects of 2-pyridylethylamine. In the presence of cimetidine a decrease in all parameters with the exception of sinus rate was observed with both histamine and 2-pyridylethylamine. 6 The selective histamine H1-receptor antagonist, mepyramine, had little effect on responses to all three agonists. However, the depressant effects observed with histamine and 2-pyridylethylamine in the presence of cimetidine were antagonized by mepyramine. 7 The results indicate the important role of the histamine H2-receptor in the mediation of the gross cardiac effects of histamine and also indicate that histamine H1-receptors can mediate cardiac depression.     

Evaluation of the role of Histamine H1- and H2-receptors in cutaneous inflammation in the guinea-pig produced by histamine and mast cell degranulation.

1 The role of histamine H1- and H2-receptors in mediating the cutaneous inflammatory response produced by exogenous histamine and the release of endogenous histamine from mast cells has been investigated by a method which permits simultaneous, quantitative measurement of vasodilatation, vascular permeability and oedema formation. 2 Histamine and the selective H1-receptor agonist, 2-(2-aminoethyl) pyridine, both produced vasodilatation, increased vascular permeability and oedema formation whereas the selective H2-receptor agonist, dimaprit, produced only vasodilatation. 3 Mepyramine and cimetidine both reduced the vasodilatation response to histamine, the combination of antagonists being superior to either antagonist alone. Mepyramine (but not cimetidine) virtually abolished extravascular albumin accumulation and oedema formation. 4 Mepyramine and cimetidine both reduced the vasodilatation response produced by active cutaneous anaphylaxis and compound 48/80. However, mepyramine was less effective in reducing the vascular permeability response to mast cell degranulation than to histamine. 5 In conclusion, the vasodilator response to histamine is mediated by both H1- and H2-receptors; the permeability response to histamine is mediated solely by H1-receptors. A combination of H1- and H2-receptor antagonists appears to be more effective than either antagonist alone in reducing cutaneous inflammatory reactions involving histamine.     

A vasodepressor action of histamine mediated by H2-receptor activation

The actions of histamine, 2-methylhistamine and 4-methylhistamine were studied in isolated guinea-pig lungs perfused through the pulmonary artery with Krebs solution containing 10^?5 M mepyramine. 4-Methylhistamine and 2-methylhistamine had 50.6 and 3.8%, respectively, of the vasodepressor activity of histamine in the pulmonary microcirculation. This effect was specifically antagonized by burimamide. Burimamide displayed characteristics of competitive antagonism against 4-methylhistamine, a selective H₂-receptor agonist. It was concluded that the vasodepressor effect was mediated by H₂-receptor activation.     

Influence of the endothelium on histamine-induced relaxation of rat middle cerebral arteries in vitro.

Histamine relaxed PGF2 alpha-precontracted rat isolated middle cerebral arteries (ID approximately 230 microns) concentration dependently with a pD2 of 5.31 (EC50: 5 x 10(-6) M). Cimetidine induced a concentration-dependent rightward shift of the histamine concentration-response curve of endothelium-intact arteries. The slope of the Schild plot was indistinguishable from unity, and the estimated pA2 for cimetidine was 6.14. The selective H2-receptor agonist dimaprit induced a concentration dependent relaxation of the cerebral arteries similar to that induced by histamine. This indicates that the histamine receptor mediating the relaxation in rat middle cerebral arteries belongs to the H2-receptor subtype. 2-Pyridylethylamine, a selective H1-receptor agonist, induced a small concentration-dependent contraction of the arteries with a pD2 of 4.16. Mepyramine, a selective H1-receptor antagonist had no potentiating effect on the relaxation induced by histamine, suggesting either that the contractile effect of 2-pyridylethylamine is nonselective or that H1 receptors mediating contraction are of minor importance for the overall histamine response. The selective H3-receptor agonist, (R)-alpha-methylhistamine, was without effect in a specific concentration range (10(-7)-10(-5) M) excluding participation of H3 receptors in the histamine-induced relaxation of these vessels. Indomethacin did not affect the vessel response to histamine, but removal of the endothelium and treatment of endothelium-intact arteries with 3 x 10(-6) M methylene blue induced a similar 0.5 log rightward shift of the histamine concentration-response curve.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dependence of histamine-evoked nociception on prostaglandin release

Intraarterial injection of histamine into the isolated perfused rabbit ear causes a reflex fall in mean arterial blood pressure by stimulation of perivascular pain receptors. This effect is reduced by a low concentration of indomethacin (1 microgram/ml). The histamine H1-receptor antagonist mepyramine (10 micrograms/ml) reduced the effect of histamine. However, it also reduced the effect of acetylcholine. The histamine H2-receptor antagonist cimetidine (3-10 micrograms/ml) did not reduce the effect of histamine. Exogenously applied phospholipase A2 did not stimulate pain receptors on its own but enhanced the algesic effect of histamine, acetylcholine or bradykinin. This enhancement was abolished by indomethacin. Prostacyclin also enhanced the effect of histamine. The results suggest that histamine releases prostaglandins (E-type and prostacyclin) which in turn render the 'pain receptors' more sensitive to histamine. This effect may be of importance in inflammatory pain in that the effect of algogens (including histamine) is enhanced by an increased phospholipase A2-mediated synthesis of prostaglandins. Not only endogenously activated phospholipase A2 is able to split off prostaglandin precursors followed by subsequent generation of prostaglandins but also exogenously administered phospholipase A2 is able to induce the release of pain-enhancing prostaglandins.     

Histamine receptors in the guinea-pig duodenum

Guinea-pig duodenum contracted by histamine or by acetylcholine was relaxed dose-dependently by a series of H₂-receptor selective agonists namely dimaprit, impromidine, clonidine and tolazoline. This relaxation was not neurally mediated since it was not modified by tetrodotoxin nor was it exerted through sympathetic receptors because it was not modified by pretreatment with propranolol or phentolamine. Apparently it was connected with the H₂-receptor stimulation more than to peculiarities of the single compounds. However a series of H₂-blockers (metiamide, cimetidine, ranitidine or oxmetidine) were unable to counteract the effect of the H₂-agonists or the relaxant effect of histamine in the presence of chlorpheniramine. This peculiar situation seems to indicate the existence of anomalous H₂-receptors, susceptible to the action of the agonists but not to that of the antagonists.     

Separate receptors mediating the positive inotropic and chronotropic effect of histamine in guinea-pig atria

The direct positive inotropic effect of histamine was studied on paced left atrial preparations from guinea pigs. Histamine (10^?8 to 10^?4 M) increased the maximum tension developed in left atria incubated at 35°C and driven at 2 Hz. The maximum increase in tension was 60% of that observed with norepinephrine. Metiamide (3 × 10^?5 M; a specific H₂-receptor antagonist) did not alter the inotropic response of left atria to histamine. However, tripelennamine (a typical H₁-receptor antagonist) competitively shifted the histamine inotropic dose—response curve to the right at concentrations from 10^?8 to 10^?7 M. Higher concentrations (3 × 10^?7 and 10^?6 M) caused little further additional shift to the right. The positive chronotropic effect of histamine on spontaneously beating atria was competitively antagonized by metiamide (10^?6 and 3 × 10^?6 M). These results demonstrate that in guinea-pig atria histamine increases myocardial contractility by an interaction with receptors closely related to classical H₁-receptors while its chronotropic effects is mediated by interaction with H₂-receptors.     

Inflammatory oedema induced by Lachesis muta muta (Surucucu) venom and LmTX-I in the rat paw and dorsal skin

The ability of crude venom and a basic phospholipase A₂ (LmTX-I) from Lachesis muta muta venom to increase the microvascular permeability in rat paw and skin was investigated. Crude venom or LmTX-I were injected subplantarly or intradermally and rat paw oedema and dorsal skin plasma extravasation were measured. Histamine release from rat peritoneal mast cell was also assessed. Crude venom or LmTX-I induced dose-dependent rat paw oedema and dorsal skin plasma extravasation. Venom-induced plasma extravasation was inhibited by the histamine H₁ antagonist mepyramine (6 mg/kg), histamine/5-hydroxytriptamine antagonist cyproheptadine (2 mg/kg), cyclooxygenase inhibitor indomethacin (5 mg/kg), nitric oxide synthesis inhibitor l-NAME (100 nmol/site), tachykinin NK₁ antagonist SR140333 (1 nmol/site) and bradykinin B₂ receptor antagonist Icatibant (0.6 mg/kg). Platelet-activating factor (PAF) antagonist PCA4248 (5 mg/kg) had no effect. LmTX-I-induced skin extravasation was inhibited by cyproheptadine, mepyramine, indomethacin and PCA4248, while l-NAME and SR140333 had no effect. Additionally, both Lachesis muta muta venom and LmTX-I concentration-dependently induced histamine release from rat mast cells. In conclusion, Lachesis muta muta venom and LmTX-I increase microvascular permeability by mechanisms involving in vivo mast cell activation and arachidonic acid metabolites. Additionally, crude venom-induced responses also involve substance P, nitric oxide and bradykinin release, whether LmTX-I-induced responses involve PAF.     

Ciproxifan and chemically related compounds are highly potent and selective histamine H3-receptor antagonists

We determined the affinities of five newly synthesized histamine H₃-receptor antagonists in an H₃-receptor binding assay and their potencies in a functional H₃-receptor model. Furthermore, we determined their potencies in a histamine H₂- and H₁-receptor model. The compounds differ from histamine in that the ethylamine side chain is replaced by an aryl-substituted propyloxy chain and they differ from one another by varying substituents of the aryl rest. Iodoproxyfan, a highly potent and selective antagonist at H₃ receptors, is structurally related to these five compounds. The specific binding of [³H]-N ^α-methylhistamine to rat brain cortex membranes was monophasically displaced by each of the five compounds at pK _i values ranging from 8.24 to 9.27. Inhibition by histamine of the electrically evoked tritium overflow from mouse brain cortex slices preincubated with [³H]noradrenaline was antagonized by all compounds and the concentration-response curve was shifted to the right with apparent pA ₂ values ranging from 7.78 to 9.39. The five compounds under study possess negligible potencies at histamine H₂ and H₁ receptors studied in the guinea-pig right atrium and ileum, respectively (pD’₂ or pK _p values ≤5.2). The present paper shows that the five compounds under study possess high affinities and potencies at histamine H₃ receptors, four out of the five compounds in this respect being equipotent with iodoproxyfan. Like iodoproxyfan, the five compounds show an at least 1000-fold selectivity for H₃ as compared to H₂ and H₁ receptors. Received: 23 June 1998 / Accepted: 21 September 1998