Research Letter: Structural Combination of Established 5‐HT<sub>2A</sub> Receptor Ligands: New Aspects of the Binding Mode

Kramer, Vasko; Herth, Matthias M.; Santini, Martin A.; Palner, Mikael; Knudsen, Gitte M.; Rösch, Frank

doi:10.1111/j.1747-0285.2010.01011.x

Cited by 6 publications

(4 citation statements)

References 13 publications

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“…Doses, concentrations and pretreatment administration time were chosen according to the pharmacodynamic properties of each drug (Andrew and Johnston, 1979;Bonhaus et al, 1999;Fletcher et al, 1996;Kennett et al, 1997;Kramer et al, 2010;Sur et al, 1998) and on the basis of previous studies reporting its selectivity toward the targeted site (Assié et al, 2005;Auclair et al, 2010;Cunningham et al, 2012;Devroye et al, 2018;Ichikawa and Meltzer, 2000;Muller et al, 2007;Navailles et al, 2008;Tao et al, 2000;Tao and Auerbach, 2002).…”

Section: Pharmacological Treatmentsmentioning

confidence: 99%

Serotonin2B receptors in the rat dorsal raphe nucleus exert a GABA-mediated tonic inhibitory control on serotonin neurons

Cathala

Devroye

Drutel

et al. 2019

Experimental Neurology

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The central serotonin 2B receptor (5-HT 2B R) is a well-established modulator of dopamine (DA) neuron activity in the rodent brain. Recent studies in rats have shown that the effect of 5-HT 2B R antagonists on accumbal and medial prefrontal cortex (mPFC) DA outflow results from a primary action in the dorsal raphe nucleus (DRN), where they activate 5-HT neurons innervating the mPFC. Although the mechanisms underlying this interaction remain largely unknown, data in the literature suggest the involvement of DRN GABAergic interneurons in the control of 5-HT activity. The present study examined this hypothesis using in vivo (intracerebral microdialysis) and in vitro (immunohistochemistry coupled to reverse transcription-polymerase chain reaction) experimental approaches in rats. Intraperitoneal (0.16 mg/kg) or intra-DRN (1 µM) administration of the selective 5-HT 2B R antagonist RS 127445 increased 5-HT outflow in both the DRN and the mPFC, these effects being prevented by the intra-DRN perfusion of the GABA A antagonist bicuculline (100 µM), as well as by the subcutaneous (0.16 mg/kg) or the intra-DRN (0.1 µM) administration of the selective 5-HT 1A R antagonist WAY 100635. The increase in DRN 5-HT outflow induced by the intra-DRN administration of the selective 5-HT reuptake inhibitor citalopram (0.1 µM) was potentiated by the intra-DRN administration (0.5 µM) of RS 127445 only in the absence of bicuculline perfusion. Finally, in vitro experiments revealed the presence of the 5-HT 2B R mRNA on DRN GABAergic interneurons. Altogether, these results show that, in the rat DRN, 5-HT 2B Rs are located on GABAergic interneurons, and exert a tonic inhibitory control on 5-HT neurons innervating the mPFC.

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Section: Pharmacological Treatmentsmentioning

confidence: 99%

Serotonin2B receptors in the rat dorsal raphe nucleus exert a GABA-mediated tonic inhibitory control on serotonin neurons

Cathala

Devroye

Drutel

et al. 2019

Experimental Neurology

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“…The 5-HT 2A receptor activation by CIMBI-5 was measured on GF62 cells using a phosphoinositide hydrolysis assay as previously described (16). Briefly, cells were incubated with myo-(1,2)-3 H-inositol (Amersham) in labeling medium.…”

Section: In Vitro Binding and Activationmentioning

confidence: 99%

Radiosynthesis and Evaluation of ¹¹C-CIMBI-5 as a 5-HT_2A Receptor Agonist Radioligand for PET

Ettrup¹,

Palner²,

Gillings³

et al. 2010

J Nucl Med

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PET brain imaging of the serotonin 2A (5-hydroxytryptamine 2A, or 5-HT 2A ) receptor has been widely used in clinical studies, and currently, several well-validated radiolabeled antagonist tracers are used for in vivo imaging of the cerebral 5-HT 2A receptor. Access to 5-HT 2A receptor agonist PET tracers would, however, enable imaging of the active, high-affinity state of receptors, which may provide a more meaningful assessment of membrane-bound receptors. In this study, we radiolabel the highaffinity 5-HT 2A receptor agonist 2-(4-iodo-2,5-dimethoxyphenyl)-N-(2-[ 11 C-OCH 3 ]methoxybenzyl)ethanamine ( 11 C-CIMBI-5) and investigate its potential as a PET tracer. Methods: The in vitro binding and activation at 5-HT 2A receptors by CIMBI-5 was measured with binding and phosphoinositide hydrolysis assays. Ex vivo brain distribution of 11 C-CIMBI-5 was investigated in rats, and PET with 11 C-CIMBI-5 was conducted in pigs. Results: In vitro assays showed that CIMBI-5 was a high-affinity agonist at the 5-HT 2A receptor. After intravenous injections of 11 C-CIMBI-5, ex vivo rat studies showed a specific binding ratio of 0.77 6 0.07 in the frontal cortex, which was reduced to cerebellar levels after ketanserin treatment, thus indicating that 11 C-CIMBI-5 binds selectively to the 5-HT 2A receptor in the rat brain. The PET studies showed that the binding pattern of 11 C-CIMBI-5 in the pig brain was in accordance with the expected 5-HT 2A receptor distribution. 11 C-CIMBI-5 gave rise to a cortical binding potential of 0.46 6 0.12, and the target-to-background ratio was similar to that of the widely used 5-HT 2A receptor antagonist PET tracer 18 F-altanserin. Ketanserin treatment reduced the cortical binding potentials to cerebellar levels, indicating that in vivo 11 C-CIMBI-5 binds selectively to the 5-HT 2A receptor in the pig brain. Conclusion: 11 C-CIMBI-5 showed a cortex-to-cerebellum binding ratio equal to the widely used 5-HT 2A antagonist PET tracer 18 F-altanserin, indicating that 11 C-CIMBI-5 has a sufficient targetto-background ratio for future clinical use and is displaceable by ketanserin in both rats and pigs. Thus, 11 C-CIMBI-5 is a promising tool for investigation of 5-HT 2A agonist binding in the living human brain.

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“…In the early 2010s, taking into account that altanserin (2), MH.MZ ( 53) and (+)-MDL-100907 (Volinanserin, 54) (Figure 12) are structurally similar to benzoylpiperidine compounds, Kramer et al decided to combine the structural elements of these well-known 5-HT 2A selective antagonists to better evaluate the binding mode of these compounds and to improve the binding properties of the newly developed derivatives [15]. Among the synthesized compounds, 55 was characterized by a benzoylpiperidine fragment (Figure 12).…”

Section: Armentioning

confidence: 99%

The Benzoylpiperidine Fragment as a Privileged Structure in Medicinal Chemistry: A Comprehensive Review

Bononi,

Lonzi,

Tuccinardi

et al. 2024

Molecules

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The phenyl(piperidin-4-yl)methanone fragment (here referred to as the benzoylpiperidine fragment) is a privileged structure in the development of new drugs considering its presence in many bioactive small molecules with both therapeutic (such as anti-cancer, anti-psychotic, anti-thrombotic, anti-arrhythmic, anti-tubercular, anti-parasitic, anti-diabetic, and neuroprotective agents) and diagnostic properties. The benzoylpiperidine fragment is metabolically stable, and it is also considered a potential bioisostere of the piperazine ring, thus making it a feasible and reliable chemical frame to be exploited in drug design. Herein, we discuss the main therapeutic and diagnostic agents presenting the benzoylpiperidine motif in their structure, covering articles reported in the literature since 2000. A specific section is focused on the synthetic strategies adopted to obtain this versatile chemical portion.

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Research Letter: Structural Combination of Established 5‐HT_2A Receptor Ligands: New Aspects of the Binding Mode

Cited by 6 publications

References 13 publications

Serotonin2B receptors in the rat dorsal raphe nucleus exert a GABA-mediated tonic inhibitory control on serotonin neurons

Serotonin2B receptors in the rat dorsal raphe nucleus exert a GABA-mediated tonic inhibitory control on serotonin neurons

Radiosynthesis and Evaluation of ¹¹C-CIMBI-5 as a 5-HT_2A Receptor Agonist Radioligand for PET

The Benzoylpiperidine Fragment as a Privileged Structure in Medicinal Chemistry: A Comprehensive Review

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Research Letter: Structural Combination of Established 5‐HT2A Receptor Ligands: New Aspects of the Binding Mode

Cited by 6 publications

References 13 publications

Serotonin2B receptors in the rat dorsal raphe nucleus exert a GABA-mediated tonic inhibitory control on serotonin neurons

Serotonin2B receptors in the rat dorsal raphe nucleus exert a GABA-mediated tonic inhibitory control on serotonin neurons

Radiosynthesis and Evaluation of 11C-CIMBI-5 as a 5-HT2A Receptor Agonist Radioligand for PET

The Benzoylpiperidine Fragment as a Privileged Structure in Medicinal Chemistry: A Comprehensive Review

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Research Letter: Structural Combination of Established 5‐HT_2A Receptor Ligands: New Aspects of the Binding Mode

Radiosynthesis and Evaluation of ¹¹C-CIMBI-5 as a 5-HT_2A Receptor Agonist Radioligand for PET