Dimeric carbamoylguanidine-type histamine H2 receptor ligands: A new class of potent and selective agonists

Kagermeier, Nicole; Werner, Kristin; Keller, Max; Baumeister, Paul; Bernhardt, Günther; Seifert, Roland; Buschauer, Armin

doi:10.1016/j.bmc.2015.01.012

Cited by 24 publications

(62 citation statements)

References 28 publications

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“…Homo- ( 5 and 53 – 60 ) and heterodimeric ( 61 – 63 ) as well as monomeric ( 127 – 141 and 145 ) hetarylpropylguanidine-type HR ligands were obtained in excellent yield by a six-step synthesis. The replacement of the imidazolyl by an aminothiazolyl moiety led, in accordance with previous reports on acylguanidine- and carbamoylguanidine-type HR ligands, 9 , 10 , 22 to highly selective and potent H 2 R agonists. The variation of the spacer length revealed best results for compounds containing a C 8 -, C 10 -, or C 12 -spacer ( 5 , 56 – 59 , and 61 – 63 ).…”

Section: Summary and Conclusionsupporting

confidence: 90%

“… 9 Insufficient chemical stability of these acylguanidines, due to hydrolytic cleavage, led to carbamoylguanidine-type H 2 R agonists, which proved to be stable. 10 As many class A GPCRs were reported to form homo- and heterodimers, bivalent ligands can potentially be used as pharmacological tools to investigate the binding mode. 11 , 12 Using different spacer lengths, Birnkammer et al showed that an interaction of the second pharmacophore with an allosteric binding site at the same receptor protomer is more likely than binding to the second orthosteric binding site of an H 2 R homodimer.…”

Section: Introductionmentioning

confidence: 99%

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Highly Potent, Stable, and Selective Dimeric Hetarylpropylguanidine-Type Histamine H₂ Receptor Agonists

et al. 2018

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On the basis of the long-known prototypic pharmacophore 3-(1H-imidazol-4-yl)propylguanidine (SK&F 91486, 2), monomeric, homodimeric, and heterodimeric bisalkylguanidine-type histamine H2 receptor (H2R) agonists with various alkyl spacers were synthesized. Aiming at increased H2R selectivity of the ligands, the imidazol-4-yl moiety was replaced by imidazol-1-yl, 2-aminothiazol-5-yl or 2-amino-4-methylthiazol-5-yl according to a bioisosteric approach. All compounds turned out to be partial or full agonists at the h/gp/rH2R. The most potent analogue, the thiazole-type heterodimeric ligand 63 (UR-Po461), was a partial agonist (Emax = 88%) and 250 times more potent than histamine (pEC50: 8.56 vs 6.16, gpH2R, atrium). The homodimeric structures 56 (UR-Po395) and 58 (UR-Po448) exhibited the highest hH2R affinities (pKi: 7.47, 7.33) in binding studies. Dimeric amino(methyl)thiazole derivatives, such as 58, generated an increased hH2R selectivity compared to the monomeric analogues, e.g., 139 (UR-Po444). Although monomeric ligands showed up lower affinities and potencies at the H2R, compounds with a short alkylic side chain like 129 (UR-Po194) proved to be highly affine hH4R ligands.

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Section: Summary and Conclusionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Highly Potent, Stable, and Selective Dimeric Hetarylpropylguanidine-Type Histamine H₂ Receptor Agonists

et al. 2018

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“…However, guanidine-based histamine H 2 R ligands demonstrate additional H 3 R antagonist potencies. Recently, Buschauer et al investigated dimeric carbamoylguanidine derivatives for the synthesis of potent H 2 R agonists (Kagermeier et al, 2015 ). Compounds containing two imidazole moieties, display selectivity for H 3 R and H 2 R in radioligand competition binding studies, whereas compound 5 (Figure 3 ) shows high H 2 R affinity with simultaneous high H 3 R inhibitory affinity.…”

Section: H 3 R/h 2 Rmentioning

confidence: 99%

Multiple Targeting Approaches on Histamine H3 Receptor Antagonists

et al. 2016

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With the very recent market approval of pitolisant (Wakix®), the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures.

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“…Coming from the lead structure SK&F 91486 (Figure ) , several potent ligands for HR subtypes, especially the hH 2 R, hH 3 R, and hH 4 R, were synthesized containing an aromatic heterocycle (imidazole and aminothiazole) and a substituted guanidine partial structure linked with a methylene spacer. Aiming at selectivity for the respective receptors, a series of alkylated, acylated, carbamoylated guanidines as well as cyanoguanidines, were identified as potent HR agents. Previous studies have already investigated the influence of substituted cyanoguanidines on the activity of HR subtypes .…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of heteroalicyclic cyanoguanidines at histamine receptors

Soliman

Wang

Zagotto

et al. 2019

Archiv der Pharmazie

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Recent studies on histamine receptor (HR) subtypes identified imidazolyl butyl cyanoguanidines, like UR-PI376, as highly potent agonists at the human histamine H 4 receptor (hH 4 R). While imidazole-containing compounds display drawbacks in pharmacokinetics, we studied the possibility of replacing the heteroaromatic cycle by nonaromatic six-membered heterocycles (piperidine, morpholine, thiomorpholine, and N-methylpiperazine) as potential bioisosteres. Beyond that, this approach should give more information about the indispensability of the aromatic ring as a basic head group. Besides these changes, a variation of the spacer length (C 3 -C 5 ) connecting the heterocycle and the cyanoguanidine moiety has been made to possibly trigger the selectivity towards the respective HRs. Investigations in radioligand-binding assays exhibited only very weak activity at the hH 1 R and hH 3 R, while nearly all compounds were inactive at the hH 2 R and hH 4 R. In the case of piperidine-containing compounds, moderate affinities at the hH 3 R over the single-digit micromolar range were detected. K E Y W O R D S

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Dimeric carbamoylguanidine-type histamine H2 receptor ligands: A new class of potent and selective agonists

Cited by 24 publications

References 28 publications

Highly Potent, Stable, and Selective Dimeric Hetarylpropylguanidine-Type Histamine H₂ Receptor Agonists

Highly Potent, Stable, and Selective Dimeric Hetarylpropylguanidine-Type Histamine H₂ Receptor Agonists

Multiple Targeting Approaches on Histamine H3 Receptor Antagonists

Synthesis and biological evaluation of heteroalicyclic cyanoguanidines at histamine receptors

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Dimeric carbamoylguanidine-type histamine H2 receptor ligands: A new class of potent and selective agonists

Cited by 24 publications

References 28 publications

Highly Potent, Stable, and Selective Dimeric Hetarylpropylguanidine-Type Histamine H2 Receptor Agonists

Highly Potent, Stable, and Selective Dimeric Hetarylpropylguanidine-Type Histamine H2 Receptor Agonists

Multiple Targeting Approaches on Histamine H3 Receptor Antagonists

Synthesis and biological evaluation of heteroalicyclic cyanoguanidines at histamine receptors

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Highly Potent, Stable, and Selective Dimeric Hetarylpropylguanidine-Type Histamine H₂ Receptor Agonists

Highly Potent, Stable, and Selective Dimeric Hetarylpropylguanidine-Type Histamine H₂ Receptor Agonists