First Metal-Containing Histamine H3 Receptor Ligands

Sander, Kerstin; Kottke, Tim; Hoffend, Claas; Walter, Miriam; Weizel, Lilia; Camelin, Jean-Claude; Ligneau, Xavier; Schneider, Erich H.; Seifert, Roland; Schwartz, Jean‐Charles; Stark, Holger

doi:10.1021/ol100419y

Cited by 21 publications

(14 citation statements)

References 30 publications

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“…After purification (as described for compound P3 ), the resulting light solid was crystallized as hydrochloride from 2-propanol (1.5 g, 50%; Scheme 1). 31,36,37 Chemical formula: C 15 H 23 NO 2 × HCl. 1 H NMR (DMSO- d 6 ): δ 10.74 (br s, 1H, NH), 7.23 (d, J =8.6, 2H, ph-2,5 H ), 6.90 (d, J =8.6, 2H, ph-3,5 H ), 4.43 (s, 2H, C H 2 –OH), 4.04 (t, J =6.0, 2H, prop-1 H 2 ), 3.43 (m, 2H, pip-2,6 H eq ), 3.16–3.13 (m, 2H, prop-3 H 2 ), 2.92–2.76 (m, 2H, pip-2,6 H ax ), 2.23–2.19 (m, 2H, prop-2 H 2 ), 1.85–1.78 (m, 5H, pip-3,5 H 2 , pip-4 H eq ), 1.45–1.34 (m, 1H, pip-4 H ax ).…”

Section: Methodsmentioning

confidence: 99%

Anticonvulsant effects of isomeric nonimidazole histamine H3 receptor antagonists

Sadek

Saad

Schwed

et al. 2016

DDDT

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Phenytoin (PHT), valproic acid, and modern antiepileptic drugs (AEDs), eg, remacemide, loreclezole, and safinamide, are only effective within a maximum of 70%–80% of epileptic patients, and in many cases the clinical use of AEDs is restricted by their side effects. Therefore, a continuous need remains to discover innovative chemical entities for the development of active and safer AEDs. Ligands targeting central histamine H3 receptors (H3Rs) for epilepsy might be a promising therapeutic approach. To determine the potential of H3Rs ligands as new AEDs, we recently reported that no anticonvulsant effects were observed for the (S)-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propanamide (1). In continuation of our research, we asked whether anticonvulsant differences in activities will be observed for its R-enantiomer, namely, (R)-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propaneamide (2) and analogs thereof, in maximum electroshock (MES)-, pentylenetetrazole (PTZ)-, and strychnine (STR)-induced convulsion models in rats having PHT and valproic acid (VPA) as reference AEDs. Unlike the S-enantiomer (1), the results show that animals pretreated intraperitoneally (ip) with the R-enantiomer 2 (10 mg/kg) were moderately protected in MES and STR induced models, whereas proconvulsant effect was observed for the same ligand in PTZ-induced convulsion models. However, animals pretreated with intraperitoneal doses of 5, 10, or 15 mg/kg of structurally bulkier (R)-enantiomer (3), in which 3-piperidinopropan-1-ol in ligand 2 was replaced by (4-(3-(piperidin-1-yl)propoxy)phenyl)methanol, and its (S)-enantiomer (4) significantly and in a dose-dependent manner reduced convulsions or exhibited full protection in MES and PTZ convulsions model, respectively. Interestingly, the protective effects observed for the (R)-enantiomer (3) in MES model were significantly greater than those of the standard H3R inverse agonist/antagonist pitolisant, comparable with those observed for PHT, and reversed when rats were pretreated with the selective H3R agonist R-(α)-methyl-histamine. Comparisons of the observed antagonistic in vitro affinities among the ligands 1–6 revealed profound stereoselectivity at human H3Rs with varying preferences for this receptor subtype. Moreover, the in vivo anticonvulsant effects observed in this study for ligands 1–6 showed stereoselectivity in different convulsion models in male adult rats.

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Section: Methodsmentioning

confidence: 99%

Anticonvulsant effects of isomeric nonimidazole histamine H3 receptor antagonists

Sadek

Saad

Schwed

et al. 2016

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“…Recently, Starks group has reported a similar example of a bioisosteric replacement of phenyl group with ferrocenyl groups targeting human histamine H 3 receptors (HH 3 R) in the central nervous system (CNS). [25] The work involved the synthesis of ferrocene-containing HH 3 R antagonists 60 by employing a CuAAC reaction and the evaluation of the binding behavior towards the receptor. The ligand was carefully designed according to the known structural blueprint of HH 3 R antagonists, with one part of the molecule bearing 1-(3-phenoxypropyl)piperidine and a lipophilic residue in the other end (Scheme 19).…”

Section: Bioconjugatesmentioning

confidence: 99%

“…Recently, Stark’s group has reported a similar example of a bioisosteric replacement of phenyl group with ferrocenyl groups targeting human histamine H 3 receptors (HH 3 R) in the central nervous system (CNS) 25. The work involved the synthesis of ferrocene‐containing HH 3 R antagonists 60 by employing a CuAAC reaction and the evaluation of the binding behavior towards the receptor.…”

Section: Bioconjugatesmentioning

confidence: 99%

10 Years of Click Chemistry: Synthesis and Applications of Ferrocene‐Derived Triazoles

Ganesh

Sudhir

Kundu

et al. 2011

Chemistry An Asian Journal

121

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Click chemistry has played a significant role as a rapid and versatile strategy for conjugating two molecular fragments under very mild reaction conditions. Introduction of ferrocene-derived triazole systems using click chemistry has attracted enormous interest in various fields due to its potential applications in electrochemical techniques for detection and sensing. The present discussion focuses on the synthesis of ferrocene-triazole and the importance of using a CuAAC reaction for such conjugation. Applications of ferrocene-based click reactions in conjugate chemistry, asymmetric catalysis, medicinal chemistry, host-guest interactions, and materials chemistry have been highlighted.

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“…A comparable approach that was recently performed with lipophilic sandwich complex-containing residues resulted in the design of centrally acting H 3 R pharmacological tools. 56) In contrast, kojic acid derivatives 6 and 7 represent novel lead compounds offering promising possibilities for the development of peripherally acting H 3 R antagonist/inverse agonists.…”

Section: H]nmentioning

confidence: 99%

Kojic Acid Derivatives as Histamine H3 Receptor Ligands

et al. 2010

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The histamine H 3 receptor (H 3 R) is a promising target in the development of new compounds for the treatment of mainly centrally occurring diseases. However, emerging novel therapeutic concepts have been introduced and some indications in the H 3 R field, e.g. migraine, pain or allergic rhinitis, might take advantage of peripherally acting ligands. In this work, kojic acid-derived structural elements were inserted into a well established H 3 R antagonist/inverse agonist scaffold to investigate the bioisosteric potential of g-pyranones with respect to the different moieties of the H 3 R pharmacophore. The most affine compounds showed receptor binding in the low nanomolar concentration range. Evaluation and comparison of kojic acid-containing ligands and their corresponding phenyl analogues (3-7) revealed that the newly integrated scaffold greatly influences chemical properties (S Log P, topological polar surface area (tPSA)) and hence, potentially modifies the pharmacokinetic profile of the different derivatives. Benzyl-1-(4-(3-(piperidin-1-yl)propoxy)phenyl)methanamine ligands 3 and 4 belong to the centrally acting diamine-based class of H 3 R antagonist/inverse agonist, whereas kojic acid analogues 6 and 7 might act peripherally. The latter compounds state promising lead structures in the development of H 3 R ligands with a modified profile of action.

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First Metal-Containing Histamine H₃ Receptor Ligands

Cited by 21 publications

References 30 publications

Anticonvulsant effects of isomeric nonimidazole histamine H<sub>3</sub> receptor antagonists

Anticonvulsant effects of isomeric nonimidazole histamine H<sub>3</sub> receptor antagonists

10 Years of Click Chemistry: Synthesis and Applications of Ferrocene‐Derived Triazoles

Kojic Acid Derivatives as Histamine H3 Receptor Ligands

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