Structure-Activity Relationships of Histamine H2-Agonists, a New Class of Positive Inotropic Drugs

Buschauer, Armin; Baumann, Gert

doi:10.1007/978-3-0348-7309-3_15

Cited by 9 publications

(9 citation statements)

References 33 publications

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“…Interestingly, the same mRNA was found in both stomach and heart, suggesting that the same molecular species mediates the actions of HA in these tissues. This is consistent with the hypothesis that the marked differences in potency of some H2-receptor antagonists in stomach and heart are related to bioavailability factors rather than to receptor heterogeneity (25,26). Hence, the absence of corresponding mRNA in dog (8) and rat heart (12) is presumably not due to the existence of a distinct cardiac isoreceptor but rather to the absence of expression of H2 receptors in the heart of these two species, as suggested by the lack of HA-induced stimulation of adenylyl cyclase (24).…”

Section: Discussionsupporting

confidence: 90%

Expression of a cloned rat histamine H2 receptor mediating inhibition of arachidonate release and activation of cAMP accumulation.

Traiffort

Ruat

Arrang

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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A DNA, cloned after screening a rat genomic bank with probes derived from the sequence of a putative dog histamine H2 receptor [Gantz, I., Schiffer, M., Delvalle, J., Logsdon, C., Campbell, V., Uhler, M. & Yamada, T. (1991) Proc. Nad. Acad. Sci. USA 88,[429][430][431][432][433], was used to prepare a probe for Northern blot analysis and to transfect Chinese hamster ovary (CHO) cells. Distribution of the gene transcripts in guinea pig tissues was consistent with that of H2 receptors. Transfected CHO cells expressed a high density of sites binding [125I]iodoaminopotentidine, a selective H2-receptor ligand.These sites were characterized as typical H2 receptors by using a series of competing agents that displayed apparent dissociation constants closely similar to corresponding values at a reference biological system. In transfected cells, histamine stimulated, with high potency and large receptor reserve, the accumulation of cAMP. In addition, in the same cells, histamine potently inhibited the release of arachidonic acid induced either by stimulation of constitutive purinergic receptors or by application of a Ca2+ ionophore. This inhibition was independent of either cAMP or Ca2+ levels. The results suggest that a single H2 receptor may be linked not only to adenylyl cyclase activation but also to reduction of phospholipase A2 activity.Because HI receptors have been reported to stimulate arachidonic acid release, inhibition of this release, an unexpected signaling pathway for H2 receptors, may account for the opposing physiological responses elicited in many tissues by stimulation of these two receptor subtypes.Histamine (HA), a ubiquitous cell-to-cell messenger, exerts its numerous actions in the nervous, endocrine, and immune systems through interaction with three pharmacologically distinct receptor subtypes, termed H1, H2, and H3 (1, 2). H1 and H2 receptors are positively coupled to phospholipase C and adenylyl cyclase, respectively, whereas the intracellular signaling system of the H3 receptor is still unknown (3-5).In contrast to membrane receptors for other monoamines, molecular studies of HA receptors have just begun (6). For instance, H2-receptor peptides were identified in guinea pig brain by photoaffinity labeling (7) and, recently, canine (8) and human (9) H2-receptor genes have been cloned. Transfection of mammalian cells with these intronless genes resulted in the expression ofboth [3H]tiotidine binding sites and HA-sensitive adenylyl cyclase activity. Preliminary pharmacological characterizations of these receptors have been reported (8,9).Because molecular biological studies progressively reveal a much greater heterogeneity among receptor subtypes than previously thought (10, 11), we felt it of interest to identify and characterize receptors related to those described by Gantz et al. (8 [125I]Iodoaminopotentidine (125I-APT) was synthesized as described (7). The drugs and their sources were as follows: cimetidine, burimamide, metiamide, and dimaprit (Smith Kline & French); famotidine (Merck Sha...

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Section: Discussionsupporting

confidence: 90%

Expression of a cloned rat histamine H2 receptor mediating inhibition of arachidonate release and activation of cAMP accumulation.

Traiffort

Ruat

Arrang

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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“…Two dually fluorinated apromidine derivatives, which are known H 2 R agonists (BU-E-75 and BU-E-76), not only induced a positive inotropic effect but also reduced heart rate in Langendorff-perfused guinea pig hearts or living anaesthetised guinea pigs ( Felix et al, 1991a , 1995 ). The lack of a positive chronotropic effect is puzzling: in isolated spontaneously beating guinea pig right atria, BU-E-75 and BU-E-76 exerted potent positive chronotropic effects: pD 2 -values of 8.12 and 8.05 were compared with pD 2 -values for a positive inotropic effect in isolated paced guinea pig papillary muscles at 7.90 and 7.91, respectively ( Buschauer and Baumann 1991 ). These results clearly showed that BU-E-75 and BU-E-76 are potent agonists of H 2 -histamine receptors in the guinea pig sinus node (SA).…”

Section: Introductionmentioning

confidence: 99%

The Roles of Cardiovascular H2-Histamine Receptors Under Normal and Pathophysiological Conditions

Neumann¹,

Kirchhefer²,

Dhein³

et al. 2021

Front. Pharmacol.

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This review addresses pharmacological, structural and functional relationships among H2-histamine receptors and H1-histamine receptors in the mammalian heart. The role of both receptors in the regulation of force and rhythm, including their electrophysiological effects on the mammalian heart, will then be discussed in context. The potential clinical role of cardiac H2-histamine-receptors in cardiac diseases will be examined. The use of H2-histamine receptor agonists to acutely increase the force of contraction will be discussed. Special attention will be paid to the potential role of cardiac H2-histamine receptors in the genesis of cardiac arrhythmias. Moreover, novel findings on the putative role of H2-histamine receptor antagonists in treating chronic heart failure in animal models and patients will be reviewed. Some limitations in our biochemical understanding of the cardiac role of H2-histamine receptors will be discussed. Recommendations for further basic and translational research on cardiac H2-histamine receptors will be offered. We will speculate whether new knowledge might lead to novel roles of H2-histamine receptors in cardiac disease and whether cardiomyocyte specific H2-histamine receptor agonists and antagonists should be developed.

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“…The compounds considered and their histamine H 2 receptor agonistic potency have been published in a series of papers [8±14] and in some review articles [6,15]. Structures and pD 2 values are given in Table 2.…”

Section: Compounds and Biological Datamentioning

confidence: 99%

“…Since all compounds are full agonists like histamine, a unique mechanism of H 2 receptor binding and activation was assumed throughout the series, with the cationic guanidino group and the imidazole nitrogens as elements of the H 2 agonistic pharmacophore. The present structures are a subset of more than 200 guanidinetype H 2 histaminergics synthesized and tested in our laboratory (isolated guinea pig atrium, pD 2 values and intrinsic activities from concentration-response curves, for review, see [6]) with the ®nal goal to enable new approaches in the acute treatment of end-stage heart failure. Inotropic and vasodilating effects due to the activation of cardiovascular H 2 receptors may be superior to conventional therapy with sympathomimetics as shown by using impromidine in severly ill patients [7].…”

Section: Introductionmentioning

confidence: 99%

Improved Alignment by Weighted Field Fit in CoMFA of Histamine H2 Receptor Agonistic Imidazolylpropylguanidines

Dove

Buschauer

1999

Quant. Struct.-Act. Relat.

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More realistic description of ligand-receptor interactions in CoMFA results from alignments considering surface and ®eld properties instead of only molecular frameworks. The ®eld ®t algorithm implemented in SYBYL (Tripos Ass.) as part of the energy minimizer provides the possibility to assign individual weights to grid points. A new weighting function derives the signi®cance of grid points for the alignment of ®elds from preceding CoMFA runs, using regression coef®cients, means, and standard deviations of ®eld variables as parameters. Just in strongly diverse congeneric series, the method does not underestimate the common structure and not overweight variable, interacting regions. CoMFA of a large series of 142 histamine H 2 receptor agonistic imidazolylpropylguanidines (pD 2 values from guinea pig atrium) is presented as example. Results with three different alignments were compared: (1) exact superposition of the constant imidazolylpropylguanidine moiety, (2) SUPERIMPOSE or FIT of energy minima, (3)

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Structure-Activity Relationships of Histamine H2-Agonists, a New Class of Positive Inotropic Drugs

Cited by 9 publications

References 33 publications

Expression of a cloned rat histamine H2 receptor mediating inhibition of arachidonate release and activation of cAMP accumulation.

Expression of a cloned rat histamine H2 receptor mediating inhibition of arachidonate release and activation of cAMP accumulation.

The Roles of Cardiovascular H2-Histamine Receptors Under Normal and Pathophysiological Conditions

Improved Alignment by Weighted Field Fit in CoMFA of Histamine H2 Receptor Agonistic Imidazolylpropylguanidines

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