bu-e-75 and arpromidine

A new class of phenyl (pyridylalcyl) guanidines, acting as potent histamine H2-agonists, inhibits IgE-mediated human basophil histamine release in a nanomolar range. IC30-level of three substitutes of this group (arpromidine, BUA-75, and FRA-19) were found to be 0.02, 0.015 and 0.008 microM. The inhibition appeared with a fast onset (plateau after 10 min. preincubation) and claimed its maximum (60 +/- 2.9%, 63 +/- 1.8%, and 61 +/- 3.1%, n = 7) with 10 microM of the compounds. H2-mediated inhibition was totally blocked by 10 microM famotidine, a potent histamine H2-antagonist. The amount of anti-IgE or antigen for the initiation of the immunological release influenced the strength of inhibition of H2-agonist FRA-19 (p less than 0.05). Combined preincubation of FRA-19 with zardaverine, a cAMP-specific phosphodiesterase III/IV inhibitor, produced a synergistical inhibitory effect of leukocyte histamine release, which might explained by their different sites of action on intracellular cAMP levels. The capability of histamine to inhibit its own release is mediated by H2-receptors exclusively. New, potent H2-receptor stimulating compounds with positive inotropic effects possess additional potent anti-allergic properties.

Topics: Basophils; Cell Separation; Dimaprit; Guanidines; Histamine Release; Humans; Imidazoles; Immunoglobulin E; Impromidine; Receptors, Histamine H2; Thiourea

Histamine receptors on guinea-pig ileum submucosal arterioles (outside diameter 40-80 microns) were studied in vitro using a computer-assisted videomicroscopy system (Diamtrak). Histamine receptor agonists investigated in this study were histamine, the H1 receptor-selective compound, 2-[2-(3-fluorophenyl)-4-imidazolyl]ethanamine (VZ 20), the H2 receptor-selective compounds, dimaprit, impromidine, (+/-)-N1-[3-(4-fluorophenyl)-3-(pyridin-2-yl)propyl]- N2-[3-(1H-imidazol-4-yl)propyl]guanidine (arpromidine) and (+/-)-N1-[3-(3,4-difluorophenyl)-3-(pyridin-2-yl)propyl]- N2-[3-(1H-imidazol-4-yl)propyl]guanidine (BU-E-75), as well as the H3 receptor-selective drug, (R)-alpha-methylhistamine ((R)-alpha-MeHA). Applied to vessels at resting tone, the agonists (1 nM-300 microM) did not change arteriolar diameter. Vessels preconstricted by 10 microM noradrenaline showed similar concentration-dependent vasodilations with histamine and VZ 20 (pD2 = 5.38 and 5.36, respectively). This histamine-induced vasodilation was not affected by tetrodotoxin (0.5 microM) or indomethacin (1 microM), but was completely abolished in the presence of 1 microM of the H1 receptor antagonist, mepyramine. Calculation of the antagonist affinity of mepyramine for the histamine receptors in submucosal arterioles yielded a pA2 of 9.46. In contrast to histamine and VZ 20, the H2 receptor agonist, dimaprit, and the H3 receptor agonist, (R)-alpha-MeHA, were ineffective at preconstricted arterioles. The guanidine-type H2 receptor agonists, impromidine, apromidine and BU-E-75, produced vasodilation at noradrenaline-preconstricted arterioles (-log EC50 = 4.47, 5.30 and 5.39, respectively) but, in contrast to histamine, were ineffective at arterioles preconstricted by U-46619 (300 nM).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arterioles; Computers; Dose-Response Relationship, Drug; Guanidines; Guinea Pigs; Histamine; Ileum; Imidazoles; Impromidine; In Vitro Techniques; Male; Microscopy; Rats; Rats, Wistar; Receptors, Histamine H1; Vas Deferens; Vasodilation

Previous studies from our department revealed that congestive heart failure (CHF) is paralleled by a decrease in number of sarcolemmal beta-receptors due to excessive levels of circulating endogenous catecholamines. In contrast, the myocardial H2-receptor system proved to be not affected (Am. Heart J. 101; 569, 1981). The first clinically tested specific H2-receptor agonist impromidine (IMP) turned out to be a potent stimulator in patients with CHF which were insensitive to catecholamine stimulation (Pharmacol. Ther. 24; 165, 1984). Though the overall results of such an H2-receptor stimulation were salutary with favourable hemodynamic effects, the narrow therapeutic range, high costs of synthesis and the arrhythmogenic potential of IMP limited its broad clinical application in large scale trials. - Recently developed phenylpyridylalkylguanidines (J. Med. Chem. 32, 1963, 1989) were investigated under in vitro and in vivo conditions in the guinea-pig under physiologic and pathophysiologic conditions using IMP as reference. - Compounds tested were arpromidine (INN) (BU-E-50) and the difluorinated analogues BU-E-75 and BU-E-76, all guanidine-type H2-agonists with additional H1-antagonistic properties due to a pheniramine like moiety. In the isolated perfused heart all three new compounds were more potent in increasing cardiac contractile force and coronary flow but less effective on heart rate and less arrhythmogenic. The same could be established under in vivo conditions where BU-E-76 was more potent than BU-E-75, arpromidine and IMP, respectively, in augmenting LVdp/dt, LVP, cardiac output and systemic blood pressure, but all compounds revealed to have less chronotropic and arrhythmogenic potentials. In the vasopressin-induced acute heart failure model BU-E-76 and BU-E-75 normalized all contractile parameters in contrast to arpromidine and IMP. Within minutes it is concluded that the new H2-receptor agonists may represent a promising therapeutic improvement for treatment of CHF patients with a cardiovascular profile superior to IMP and conventional catecholamines.

Topics: Animals; Cardiac Output; Cardiotonic Agents; Guanidines; Guinea Pigs; Heart Failure; Heart Rate; Hemodynamics; Imidazoles; Impromidine; Receptors, Histamine H2; Stroke Volume; Vasopressins

Replacement of the cimetidine moiety in impromidine (1,N1-[3-(1H-imidazol-4-yl)propyl]-N2-[2-[[(5-methyl-1H-imidazol-4- yl)methyl]thio]ethyl]guanidine) by more lipophilic H2-nonspecific pheniramine-like structures resulted in potent H2 agonists with up to 160 times the activity of histamine in the isolated, spontaneously beating guinea pig right atrium. Additionally, the compounds proved to be moderate H1 antagonists. Highest H2-agonistic potency was found in compounds characterized by a three-membered carbon chain connecting the aromatic rings and the guanidine group. The activity in the atrium was increased 2-4-fold by halogen substituents in the meta or para position of the phenyl ring. Highest H1-antagonistic potency resides in the group of para-halogenated compounds, p-F representing the optimal substituent in both receptor models. The corresponding guanidine 52 (arpromidine, N1-[3-(4-fluorophenyl)-3-pyridin-2-ylpropyl]-N2-[3-(1H-imidazol-4- yl)propyl]guanidine) combines about 100 times the activity of histamine at the H2 receptor with H1-antagonistic potency in the range of pheniramine. Further increase in the activity on the atrium was achieved by disubstitution with halogen on the phenyl ring, such as 3,4-F2, 3,5-F2, and 3,4-Cl2 (63-65). The 2-pyridyl group in arpromidine was replaced by 3-pyridyl without significant change in H2 agonistic activity, whereas the 4-pyridyl and phenyl analogues were less active. The rank order of potency in the atrium was in good agreement with the positive inotropic effects found in isolated, perfused guinea pig hearts, where 63-65 were the most potent compounds as well.

Topics: Animals; Cardiotonic Agents; Chemical Phenomena; Chemistry; Guanidines; Guinea Pigs; Heart; Histamine H1 Antagonists; Imidazoles; Impromidine; In Vitro Techniques; Receptors, Histamine H2; Structure-Activity Relationship