The (S)-(+)-enantiomer of dimethindene: a novel M2-selective muscarinic receptor antagonist

Pfaff, Otmar; Hildebrandt, Caren; Waelbroeck, Magalì; Hou, Xiaomei; Moser, Ulrich; Mutschler, E.; Lambrecht, Günter

doi:10.1016/0014-2999(95)00454-7

Cited by 27 publications

(18 citation statements)

References 39 publications

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“…In agreement with the [ 3 H]mepyramine binding studies (Table 1), mepyramine (30) was about 2-fold less potent at inhibiting histamine-stimulated GTP hydrolysis in membranes expressing hH 1 R than in membranes expressing gpH 1 R (Table 3). A similar difference in potency was (Pfaff et al, 1995). Among the second-generation H 1 R antagonists 41 to 45, no significant differences in potency between hH 1 R and gpH 1 R emerged.…”

Section: Differences Between Human and Guineamentioning

confidence: 66%

Multiple Differences in Agonist and Antagonist Pharmacology between Human and Guinea Pig Histamine H₁-Receptor

Seifert¹,

Wenzel-Seifert²,

Bürckstümmer³

et al. 2003

J Pharmacol Exp Ther

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Species isoforms of histamine H 2 -, H 3 -, and H 4 -receptors differ in their pharmacological properties. The study aim was to dissect differences between the human H 1 R (hH 1 R) and guinea pig H 1 R (ghH 1 R). We coexpressed hH 1 R and gpH 1 R with regulators of G-protein signaling in Sf9 insect cells and analyzed the GTPase activity of G q -proteins. Small H 1 R agonists showed similar effects at hH 1 R and gpH 1 R, whereas bulkier 2-phenylhistamines and histaprodifens were up to ϳ10-fold more potent at gpH 1 R than at hH 1 R. Most 2-phenylhistamines and histaprodifens were more efficacious at gpH 1 R than at hH 1 R. Several first-generation H 1 R antagonists were ϳ2-fold, and arpromidine-type H 1 R antagonists up to ϳ10-fold more potent at gpH 1 R than at hH 1 R. [ The Phe-1533 Leu-153/Ile-4333 Val-433 double mutant expressed excellently but only partially changed the pharmacological properties of hH 1 R. Small H 1 R agonists and 2-phenylhistamines interacted differentially with human and guinea pig H 2 R in terms of potency and efficacy, respectively. Our data show the following: 1) there are differences in agonist-and antagonistpharmacology of hH 1 R and gpH 1 R encompassing diverse classes of bulky ligands. These differences may be explained by higher conformational flexibility of gpH 1 R relative to hH 1 R; 2) Phe-153 and Ile-433 are critical for proper folding and expression of hH 1 R; and 3) H 2 R species isoforms distinguish between H 1 R agonists.Histamine serves as a neurotransmitter and autacoid and acts through specific H x Rs designated as H 1 R, H 2 R, H 3 R, and H 4 R, respectively (Hill et al., 1997;Hough, 2001). The H 1 R couples to G q -proteins. Numerous H 1 R agonists and antagonists are known. H 1 R agonists are divided into three classes ( Fig. 1): 1) small agonists (2-4) derived from histamine (1), 2) histamine derivatives with bulkier aromatic substituents at position 2 of the imidazole ring (5-18), and 3) histaprodifens, e.g., compounds 19 to 23 Zingel et al., 1995;Elz et al., 2000). H 1 R agonists are important experimental tools to analyze H 1 R function in cellular and organ systems (Zingel et al., 1995;Hill et al., 1997). H 1 R antagonists are commonly divided into sedating (first-generation, 24-32) and nonsedating (second-generation, 41-45) antagonists (Fig. 2). Today, especially the second-generation H 1 R antagonists are of great importance for the treatment of allergic diseases (Hill et al., 1997). Guanidines 33, 34, and 36 to 39 derived from arpromidine (35) are dual H 2 R agonists/ H 1 R antagonists (Buschauer, 1989).The availability of H x R cDNAs allowed for the comparison of the pharmacological properties of H x R species isoforms in recombinant systems under identical experimental conditions. Such expression studies uncovered species differences This work was supported by the National Institutes of Health COBRE Award 1 P20 RR15563 and matching support from the State of Kansas and the University of Kansas (R.S.), a grant from the Army Research Office (DAAD 19-00-...

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Section: Differences Between Human and Guineamentioning

confidence: 66%

Multiple Differences in Agonist and Antagonist Pharmacology between Human and Guinea Pig Histamine H₁-Receptor

Seifert¹,

Wenzel-Seifert²,

Bürckstümmer³

et al. 2003

J Pharmacol Exp Ther

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“…The withdrawal of either DiM or MiH significantly impaired the developmental potency of mEPS cells in chimeric blastocysts (Figure 7E and Table S6) and led to rapid differentiation of primed hPSC-converted hEPS cells (Figure 7F). DiM has been reported to inhibit G protein coupled receptors, including the histamine and the muscarinic receptors (Pfaff et al, 1995), and MiH is known to inhibit PARP1 (Alano et al, 2006). Notably, DiM or MiH could be replaced with other inhibitors targeting the same targets for the maintenance of hEPS cells (Figure 7G).…”

Section: Resultsmentioning

confidence: 99%

Derivation of Pluripotent Stem Cells with In Vivo Embryonic and Extraembryonic Potency

Yang

Liu

et al. 2017

Cell

404

469

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SUMMARY Of all known cultured stem cell types, pluripotent stem cells (PSCs) sit atop the landscape of developmental potency and are characterized by their ability to generate all cell types of an adult organism. However, PSCs show limited contribution to the extraembryonic placental tissues in vivo. Here, we show that a chemical cocktail enables the derivation of stem cells with unique functional and molecular features from mice and humans, designated as extended pluripotent stem (EPS) cells, which are capable of chimerizing both embryonic and extraembryonic tissues. Notably, a single mouse EPS cell shows widespread chimeric contribution to both embryonic and extraembryonic lineages in vivo and permits generating single-EPS-cell-derived mice by tetraploid complementation. Furthermore, human EPS cells exhibit interspecies chimeric competency in mouse conceptuses. Our findings constitute a first step toward capturing pluripotent stem cells with extraembryonic developmental potentials in culture and open new avenues for basic and translational research.

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“…Because first-generation antihistamines are considered poorly selective, they can interfere with signal transmission of different off-target receptors, including muscarinic acetylcholine receptor and adrenergic receptors (Church 1999). Dimethindene, for example, was described with antimuscarinic activity in rodents (Pfaff et al 1995). The muscarinic system is also involved in behavior and heart rate control, and thus, interference with muscarinic receptors can cause similar effects to what we observed in our exposed larvae.…”

Section: Discussionmentioning

confidence: 99%

pH‐Dependent Uptake and Sublethal Effects of Antihistamines in Zebrafish (Danio rerio) Embryos

Bittner

Teixidó

Keddi

et al. 2019

Enviro Toxic and Chemistry

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Reported off‐target effects of antihistamines in humans draw interest in ecotoxicity testing of first‐ and second‐generation antihistamines, the latter of which have fewer reported side effects in humans. Because antihistamines are ionizable compounds, the pH influences uptake and toxicity and thus is highly relevant when conducting toxicity experiments. Zebrafish embryo toxicity tests were performed with the 3 first‐generation antihistamines ketotifen, doxylamine, and dimethindene and the 2 second‐generation antihistamines cetirizine and levocabastine at pH 5.5, 7.0, and 8.0. We detected effects on survival, phenotype, swimming activity, and heart rate for 4 antihistamines with the exception of levocabastine, which did not show any lethal or sublethal effects. When compared to lethal concentrations, effect concentrations neither of phenotype malformation nor of swimming activity or heart rate deviated by more than a factor of 10 from lethal concentrations, indicating that all sublethal effects were fairly nonspecific. First‐generation antihistamines are weak bases and showed decreasing external effect concentrations with increasing neutral fraction, accompanied by increased uptake in the fish embryo. As a result, internal effect concentrations were independent from external pH. The pH‐dependent toxicity originates from speciation‐dependent uptake, with neutral species taken up in higher amounts than the corresponding ionic species. Cetirizine, which shifts from a zwitterionic to an anionic state in the measured pH range, did not show any pH‐dependent uptake or toxicity. Environ Toxicol Chem 2019;00:1–11. © 2019 SETAC

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The (S)-(+)-enantiomer of dimethindene: a novel M2-selective muscarinic receptor antagonist

Cited by 27 publications

References 39 publications

Multiple Differences in Agonist and Antagonist Pharmacology between Human and Guinea Pig Histamine H₁-Receptor

Multiple Differences in Agonist and Antagonist Pharmacology between Human and Guinea Pig Histamine H₁-Receptor

Derivation of Pluripotent Stem Cells with In Vivo Embryonic and Extraembryonic Potency

pH‐Dependent Uptake and Sublethal Effects of Antihistamines in Zebrafish (Danio rerio) Embryos

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The (S)-(+)-enantiomer of dimethindene: a novel M2-selective muscarinic receptor antagonist

Cited by 27 publications

References 39 publications

Multiple Differences in Agonist and Antagonist Pharmacology between Human and Guinea Pig Histamine H1-Receptor

Multiple Differences in Agonist and Antagonist Pharmacology between Human and Guinea Pig Histamine H1-Receptor

Derivation of Pluripotent Stem Cells with In Vivo Embryonic and Extraembryonic Potency

pH‐Dependent Uptake and Sublethal Effects of Antihistamines in Zebrafish (Danio rerio) Embryos

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Multiple Differences in Agonist and Antagonist Pharmacology between Human and Guinea Pig Histamine H₁-Receptor

Multiple Differences in Agonist and Antagonist Pharmacology between Human and Guinea Pig Histamine H₁-Receptor