Pharmacological Characterization of the Novel Histamine H3Receptor Antagonist SCH 79687 (original) (raw)
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The Journal of pharmacology and experimental therapeutics, 2003
We present the pharmacological and pharmacokinetic profiles of a novel histamine H3 receptor antagonist, N-(3,5-dichlorophenyl)-N'-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687). The H3-receptor binding Ki values for SCH 79687 were 1.9 and 13 nM in the rat and guinea pig (GP), respectively. The Ki values for SCH 79687 at histamine H1 and H2 receptors were greater than 1 microM. SCH 79687 showed a 41- and 82-fold binding selectivity for the H3 receptor over alpha 2A-adrenoceptors and imidazoline I2, and >500-fold H3 selectivity compared with over 60 additional receptors. The pA2 value for SCH 79687 in the GP ileum electrical field-stimulated (EFS) contraction was 9.6 +/- 0.3. Similar H3 antagonist activity was observed in the EFS cryopreserved and fresh tissue isolated human saphenous vein (HSV) assays (pKb = 9.4 +/- 0.3 and 10.1 +/- 0.4). SCH 79687 (30 nM) did not block clonidine-induced inhibition of EFS-induced contractions in HSV. SCH 79687 (ED50 = 0.3 mg/kg ...
Antiallergic effects of H1-receptor antagonists
2000
The primary mechanism of antihistamine action in the treatment of allergic diseases is believed to be competitive antagonism of histamine binding to cellular receptors (speci®cally, the H 1 -receptors), which are present on nerve endings, smooth muscles, and glandular cells. This notion is supported by the fact that structurally unrelated drugs antagonize the H 1 -receptor and provide clinical bene®t. However, H 1 -receptor antagonism may not be their sole mechanism of action in treating allergic rhinitis. On the basis of in vitro and animal experiments, drugs classi®ed as H 1 -receptor antagonists have long been recognized to have additional pharmacological properties. Most ®rst-generation H 1 -antihistamines have anticholinergic, sedative, local anaesthetic, and anti-5-HT effects, which might favourably affect the symptoms of the allergic response but also contribute to side-effects. These additional properties are not uniformly distributed among drugs classi®ed as H 1 -receptor antagonists. Azatadine, for example, inhibits in vitro IgE-mediated histamine and leukotriene (LT) release from mast cells and basophils. In human challenge models, terfenadine, azatadine, and loratadine reduce IgE-mediated histamine release. Cetirizine reduces eosinophilic in®ltration at the site of antigen challenge in the skin, but not the nose. In a nasal antigen challenge model, cetirizine pretreatment did not affect the levels of histamine and prostaglandin D 2 recovered in postchallenge lavages, whereas the levels of albumin, N-tosyl-L-arginine methyl ester (TAME) esterase activity, and LTs were reduced. Terfenadine, cetirizine, and loratadine blocked allergen-induced hyperresponsiveness to methacholine. In view of the complexity of the pathophysiology of allergy, a number of H 1 antagonists with additional properties are currently under development for allergic diseases. Mizolastine, a new H 1receptor antagonist, has been shown to have additional actions that should help reduce the allergic response. In animal models, mizolastine inhibits antigeninduced eosinophil in®ltration into mouse skin and into the nasal cavity of guineapigs. Mizolastine also signi®cantly inhibits antigen-induced neutrophil in®ltration into the bronchoalveolar lavage¯uids of guinea-pigs. In addition, it inhibits arachidonic acid-induced paw oedema in rats without affecting carrageenininduced rat paw oedema, suggesting an effect on LT generation. In man, mizolastine inhibits early and late antigen-induced soluble intercellular adhesion molecule 1 (ICAM-1) levels in skin blisters. It also inhibits anaphylactic release of histamine from rodent mast cells, LTC 4 and LTB 4 release from mouse bonemarrow-derived mast cells, LTC 4 release from rat intestinal mast cells, and 5lipoxygenase activity of polymorphonuclear neutrophils of guinea-pig intestines and rat basophilic leukaemia cells. It is clear that a number of H 1 -antihistamines have multiple effects on the allergic in¯ammatory response. It is equally clear that these antiallergic effects are not uniformly shared among all drugs of this class. The assessment of the clinical signi®cance of these results and research regarding the parts of the molecules responsible for these activities are underway.
British Journal of Pharmacology, 1992
The effect of (R)-a-methylhistamine, a selective H3-histamine receptor agonist, was examined on the neurogenic hypertension and tachycardia that is induced by stimulation of areas in the medulla oblongata of guinea-pigs. Electrical medullary stimulation (32 Hz, 3-5 s trains, 0.5-1.0 ms square pulse, 25-400 juA) produced intensity-dependent increases in blood pressure and a more variable tachycardia. 2 (R)-ac-methylhistamine inhibited the hypertension and tachycardia due to submaximal CNS stimulation. The inhibition of hypertension by (R)-x-methylhistamine was dose-dependent (1O-300 tg kg-', i.v.) and was not seen at high intensities of stimulation. 3 (R)-o-methylhistamine (300 ptg kg-', i.v.) did not attenuate the pressor response to adrenaline (1 and 3 fLg kg-', i.v.), indicating that the effect of (R)-x-methylhistamine was not mediated by a postjunctional action on smooth muscle. 4 The inhibition of CNS-induced hypertension by (R)-x-methylhistamine (300 yg kg-', i.v.) was blocked by the H3 antagonists, thioperamide (ID50 = 0.39 mg kg-', iv.), impromidine (ID50 = 0.22 mg kg-, i.v.) and burimamide (ID50 = 6 mg kg-', i.v.). The rank order potency of these antagonists is consistent with activity at the H3B receptor subtype. Chlorpheniramine (30 ptg kg-', i.v.) and cimetidine (3 mg kg-', i.v.) did not antagonize the inhibition of CNS-hypertension by (R)-a-methylhistamine. 5 These results suggest that (R)-a-methylhistamine inhibits sympathetic hypertensive responses in guinea-pigs by activation of prejunctional H3-receptors, possibly located on postganglionic nerve terminals. Furthermore, on the basis of the rank order potency to different H3-antagonists, it appears that the H3B-receptor subtype is involved with H3-receptor responses on vascular sympathetic nerves.
Clinical comparison of histamine H1–receptor antagonist drugs
Journal of Allergy and Clinical Immunology, 1996
Nearly 40 million Americans have symptoms of upper respiratory alleigies, making antihistamines among the most frequently used pharmacologic agents. Although there are mediators of allergic symptoms in addition to histamine, therapy for allergic rhinitis and urticaria has focused upon the use of antihistamines. The classic histamine Hi-receptor antagonists, however, are not selective for the H 1 site and produce a variety of dopamhzergic, selvtonergic, and cholinergic responses leading to considerable adverse eff'ects in the central nervous system consequent to both their pharmacologic nonselectivi~ and their ability to penetrate the blood-brain bat74er readily. The second-generation antihistamines were a major advance in the therapy of allelgic rhinitis, because they do not penetrate the blood-brain ban'ier as rapidly and are also designed for greater specificity at Hseceptor. Given their greater selectivity for the Hseceptor, they cause fewer undesirable central nervous system actions, whereas their eficacy is similar to that of the classic antihistamines used in the treatment of allergic rhinitis. Selecting among these antihistamines for the treatment of allergic" rhinitis has focused on their phal~nacokinetics and adverse effect profiles. The potential cardiotoxic effects of some antihistamines when their metabolism is inhibited requires caution in presoibing these agents. The antiallergic and antiasthmatic e~fects of several newer antihistamines are being explored. For the cIiniciam making the therapeutic decision among H seceptor antagonists requires a comprehensive knowledge of their diverse e~[ects.
Cardiotonic agents. 6. Histamine analogs as potential cardiovascular selective H2 agonists
Journal of Medicinal Chemistry, 1990
Twenty-six alkyl and aralkyl histamine analogues were prepared as potential cardiotonic agents. Compounds were designed to allow interaction with a putative secondary aryl binding site at the Hz receptor, the presence of which was inferred from the structure of cyproheptadine, which is known to have H2-antagonist properties. The compounds were examined for inotropic activity in ferret papillary muscle. Potent inotropic activity was generally found in N-alkyl-and N,N-dialkylimidazole-4-ethanamines, whereas N-(amidoalkyl)imidazole-4-ethanamines and N-alkylimidazole-4-propanamines were at best weakly active. Five compounds were examined in screens designed to assess hemodynamic effects and gastric acid secretion in vivo. Two of these compounds, a-(3-phenyl-2-transpropenyl)-lH-imidazole-4-ethanamine and N-heptyl-lH-imidazole-4-ethanamine, showed positive inotropic activity with minimal effects on heart rate and mean arterial pressure in vivo; however, both compounds were found to stimulate gastric acid secretion. These results demonstrate that selectivity between various H2-receptor-mediated activities can be obtained with substituted histamine analogues.
Biochemical Pharmacology, 2004
Histamine H 3 receptors regulate the release of a variety of central neurotransmitters involved in cognitive processes. A-349821 ((4 0-(3-((R,R)2,5-dimethyl-pyrrolidin-1-yl)-propoxy)-biphenyl-4-yl)-morpholin-4-yl-methanone) is a novel, non-imidazole H 3 receptor ligand, displaying high affinity for recombinant rat and human H 3 receptors, with pK i values of 9.4 and 8.8, respectively, and high selectivity for the H 3 receptor versus H 1 , H 2 , and H 4 histamine receptors. A-349821 is a potent H 3 receptor antagonist in a variety of models using recombinant human and rat receptors, reversing agonist induced changes in cyclic AMP formation (pK b ¼ 8.2 and pK b ¼ 8.1, respectively), [ 35 S]-GTPgS binding (pK b ¼ 9.3 and pK b ¼ 8.6, respectively) and calcium levels (human pK b ¼ 8.3). In native systems, A-349821 competitively reversed agonist induced inhibition of electric field stimulated guinea-pig ileum (pA 2 ¼ 9.5) and histaminemediated inhibition of [ 3 H]-histamine release from rat brain cortical synaptosomes (pK b ¼ 9.2). Additionally, A-349821 inhibited constitutive GTPgS binding at both rat and human H 3 receptors with respective pEC 50 values of 9.1 and 8.6, demonstrating potent inverse agonist properties. In behavioral studies, A-349821 (0.4 mg/kg-4 mg/kg) potently blocked (R)-a-methylhistamine-induced dipsogenia in mice. The compound also enhanced cognitive activity in a five-trial inhibitory avoidance model in spontaneously hypertensive rat (SHR) pups at doses of 1-10 mg/kg, with the 1 mg/kg dose showing comparable efficacy to a fully efficacious dose of ciproxifan (3 mg/ kg). These doses of A-349821 were without effect on spontaneous locomotor activity. Thus, A-349821 is a novel, selective non-imidazole H 3 antagonist/inverse agonist with balanced high potency across species and favorable cognition enhancing effects in rats.
Mechanism of decongestant activity of α2-adrenoceptor agonists
Pulmonary Pharmacology & Therapeutics, 2008
The vascular bed in nasal mucosa of different species, including human, is highly vascularized and an extensive sinusoidal network of large capacitance vessels is present deep within the submucosa. When this network of venous sinusoids is engorged with blood, the swollen mucosa reduces the size of the airway lumen and congestion ensues. Nasal vasculature tone is strongly influenced by the sympathetic nervous system and the only drugs approved specifically to relieve vascular nasal obstruction are a-adrenoceptor sympathomimetic agents. Due to their vasoconstrictor action, the sympathomimetic decongestants oppose vasodilation, reducing nasal airway resistance and thus facilitating nose breathing. However, standard decongestants that are non-selective a-adrenoceptor agonists are associated with the potential for side-effect liabilities including hypertension, stroke, insomnia and nervousness. We propose than a selective a 2 -adrenoceptor agonist, by acting preferentially on nasal venous capacitance vessels, will elicit decongestion with a reduced side-effect liability. In the present study, we evaluated the effects of the selective a 2 -adrenoceptor agonist BHT-920 in a real-time tissue contractility assay using isolated pig nasal explants and in an in vivo cat model of congestion. The vasoconstrictor and decongestant effects of BHT-920 were compared to the non-selective a-adrenoceptor agonist epinephrine and the standard decongestant oxymetazoline. Our results showed that the a 2 -adrenoceptor agonist BHT-920 preferentially contracts venous sinusoids confirming previous observations [Corboz MR, Varty LM, Rivelli MA, Mutter JC, Mingo G, McLeod R, et al. Effects of an a 2 -adrenoceptor agonist in nasal mucosa. Arch Physiol Biochem 2003;11: 335-6, Corboz MR, Rivelli MA, Varty LM, Mutter J, Cartwright M, Rizzo CA, et al. Pharmacological characterization of postjunctional a-adrenoceptor in human nasal mucosa. Am J Rhinol 2005;19
British Journal of Pharmacology, 1992
SK&F 104856 (2‐vinyl‐7‐chloro‐3,4,5,6‐tetrahydro‐4‐methylthieno[4,3,2ef][3]benzazepine) is a novel postjunctional α.1‐ and α.2‐adrenoceptor antagonist. SK&F 104856 as well as prazosin and SK&F 86466 reduced blood pressure in the anaesthetized normotensive dog. SK&F 86466 and rauwolscine but not SK&F 104856 or prazosin, produced a marked increase in myocardial contractility which corresponds with their ability to block prejunctional α.2‐adrenoceptors. Intravenous or oral administration of SK&F 104856 resulted in dose‐dependent antihypertensive responses in 1‐kidney, 1‐clip (1‐K, 1‐C) Goldblatt hypertensive dogs with baseline blood pressure of approximately 140 mmHg. At 0.1 and 1 mg kg−1, i.v., mean arterial blood pressure fell by 11 ± 5 and 23 ± 5 mmHg, respectively. At 3 and 10 mg kg−1, p.o., blood pressure fell by 9 ± 3 and 22 ± 5 mmHg, respectively. At 10 mg kg−1, p.o., the antihypertensive effect of SK&F 104856 was still evident at 4 h. The data indicate that SK&F 104856 shows se...