Discovery of Pitolisant, the First Marketed Histamine
            <scp>
              H
              <sub>3</sub>
            </scp>
            ‐Receptor Inverse Agonist/Antagonist for Treating Narcolepsy*

Ganellin, C. Robin; Schwartz, Jean‐Charles; Stark, Holger

doi:10.1002/9783527808694.ch13

Cited by 5 publications

(5 citation statements)

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“…Furthermore, both structures,143 and 144, could be an interesting starting point for future projects facing H 3 and H 4 receptor selectivity. This is of special interest as to date there are still no drugs available for both receptors (apart from Pitolisant [61] ), although a wide field of applications are reported for the H 3 R (e. g. several neurodegenerative diseases) [21][22][23][24][25] and the H 4 R (e. g. inflammation, allergic diseases). [26][27][28][29][30]…”

Section: Discussionmentioning

confidence: 99%

Structure‐Activity Relationship of Hetarylpropylguanidines Aiming at the Development of Selective Histamine Receptor Ligands^†

et al. 2019

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New classes of alkylated hetarylpropylguanidines with different functionality and variation in spacer length were synthesized to determine their behavior at the four histamine receptor (H 1 R, H 2 R, H 3 R, H 4 R) subtypes. Alkylated guanidines with different terminal functional groups and varied basicity, like amine, guanidine and urea were developed, based on the lead structure SK&F 91486 ( 2 ). Furthermore, heteroatomic exchange at the guanidine structure of 2 led to simple analogues of the lead compound. Radioassays at all histamine receptor subtypes were accomplished, as well as organ bath studies at the guinea pig ( gp ) ileum ( gp H 1 R) and right atrium ( gp H 2 R). Ligands with terminal functionalization led to, partially, highly affine and potent structures (two digit nanomolar), which showed up a bad selectivity profile within the histamine receptor family. While the benzoylurea derivative 144 demonstrated a preference towards the human ( h ) H 3 R, S‐methylisothiourea analogue 143 obtained high affinity at the h H 4 R (pK i =8.14) with moderate selectivity. The molecular basis of the latter finding was supported by computational studies.

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Section: Discussionmentioning

confidence: 99%

Structure‐Activity Relationship of Hetarylpropylguanidines Aiming at the Development of Selective Histamine Receptor Ligands^†

et al. 2019

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“…(iii) The potencies of new H 3 -R antagonists/inverse agonists were compared to their affinities in radioligand studies in the mouse brain (Nickel et al 2001 ). The compounds had been synthesized by W. Schunack and H. Stark (Berlin), who later developed the H 3 -R inverse agonist pitolisant together with J.C. Schwartz (Paris), which has been marketed as a novel drug against narcolepsy in 2016 (Ganellin et al 2018 ). A typical property of H 3 -Rs is their constitutive activity (Rouleau et al 2002 ) and accordingly the H 3 -R inverse agonist pitolisant tended to increase noradrenaline in mouse brain cortex slices (reviewed in Schlicker and Kathmann 2016 ).…”

Section: Beyond Serotoninmentioning

confidence: 99%

Serotonin and beyond—a tribute to Manfred Göthert (1939-2019)

Bönisch

Fink

Malinowska

et al. 2021

Naunyn-Schmiedeberg's Arch Pharmacol

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Manfred Göthert, who had served Naunyn-Schmiedeberg’s Arch Pharmacol as Managing Editor from 1998 to 2005, deceased in June 2019. His scientific oeuvre encompasses more than 20 types of presynaptic receptors, mostly on serotoninergic and noradrenergic neurones. He was the first to identify presynaptic receptors for somatostatin and ACTH and described many presynaptic receptors, known from animal preparations, also in human tissue. In particular, he elucidated the pharmacology of presynaptic 5-HT receptors. A second field of interest included ligand-gated and voltage-dependent channels. The negative allosteric effect of anesthetics at peripheral nACh receptors is relevant for the peripheral clinical effects of these drugs and modified the Meyer-Overton hypothesis. The negative allosteric effect of ethanol at NMDA receptors in human brain tissue occurred at concentrations found in the range of clinical ethanol intoxication. Moreover, the inhibitory effect of gabapentinoids on P/Q Ca2+ channels and the subsequent decrease in AMPA-induced noradrenaline release may contribute to their clinical effect. Another ligand-gated ion channel, the 5-HT3 receptor, attracted the interest of Manfred Göthert from the whole animal via isolated preparations down to the cellular level. He contributed to that molecular study in which 5-HT3 receptor subtypes were disclosed. Finally, he found altered pharmacological properties of 5-HT receptor variants like the Arg219Leu 5-HT1A receptor (which was also shown to be associated with major depression) and the Phe124Cys 5-HT1B receptor (which may be related to sumatriptan-induced vasospasm). Manfred Göthert was a brilliant scientist and his papers have a major impact on today’s pharmacology.

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“…It was later discovered that H 3 Rs do not only control histamine release but also, functioning as heteroreceptors, modulate the other neurotransmitter systems, e.g., the cholinergic, , dopaminergic, noradrenergic, , and serotoninergic systems, in both the central and peripheral nervous systems. H 3 R antagonists/inverse agonists demonstrated diverse pharmacological effects in preclinical and clinical studies, highlighting the importance of various central nervous system (CNS)-related therapeutic applications, including Parkinson’s disease and Alzheimer’s disease (AD), narcolepsy, obesity, dementia, epilepsy, schizophrenia, and attention deficit hyperactivity disorder (ADHD) . Recently, many other CNS-related disorders have also been suggested as candidates for treatment by H 3 R antagonist/inverse agonist ligands: Tourette syndrome, Prader–Willi syndrome, depression, or autism …”

Section: Introductionmentioning

confidence: 99%

4-Oxypiperidine Ethers as Multiple Targeting Ligands at Histamine H₃ Receptors and Cholinesterases

Michalska,

Dzięgielewski,

Godyń

et al. 2024

ACS Chem. Neurosci.

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This study examines the properties of a novel series of 4-oxypiperidines designed and synthesized as histamine H 3 R antagonists/inverse agonists based on the structural modification of two lead compounds, viz., ADS003 and ADS009. The products are intended to maintain a high affinity for H 3 R while simultaneously inhibiting AChE or/and BuChE enzymes. Selected compounds were subjected to hH 3 R radioligand displacement and gpH 3 R functional assays. Some of the compounds showed nanomolar affinity. The most promising compound in the naphthalene series was ADS031, which contained a benzyl moiety at position 1 of the piperidine ring and displayed 12.5 nM affinity at the hH 3 R and the highest inhibitory activity against AChE (IC 50 = 1.537 μM). Eight compounds showed over 60% eqBuChE inhibition and hence were qualified for the determination of the IC 50 value at eqBuChE; their values ranged from 0.559 to 2.655 μM. Therapy based on a multitarget-directed ligand combining H 3 R antagonism with additional AChE/BuChE inhibitory properties might improve cognitive functions in multifactorial Alzheimer's disease.

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Discovery of Pitolisant, the First Marketed Histamine H ₃ ‐Receptor Inverse Agonist/Antagonist for Treating Narcolepsy*

Cited by 5 publications

References 50 publications

Structure‐Activity Relationship of Hetarylpropylguanidines Aiming at the Development of Selective Histamine Receptor Ligands^†

Structure‐Activity Relationship of Hetarylpropylguanidines Aiming at the Development of Selective Histamine Receptor Ligands^†

Serotonin and beyond—a tribute to Manfred Göthert (1939-2019)

4-Oxypiperidine Ethers as Multiple Targeting Ligands at Histamine H₃ Receptors and Cholinesterases

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Discovery of Pitolisant, the First Marketed Histamine H 3 ‐Receptor Inverse Agonist/Antagonist for Treating Narcolepsy*

Cited by 5 publications

References 50 publications

Structure‐Activity Relationship of Hetarylpropylguanidines Aiming at the Development of Selective Histamine Receptor Ligands†

Structure‐Activity Relationship of Hetarylpropylguanidines Aiming at the Development of Selective Histamine Receptor Ligands†

Serotonin and beyond—a tribute to Manfred Göthert (1939-2019)

4-Oxypiperidine Ethers as Multiple Targeting Ligands at Histamine H3 Receptors and Cholinesterases

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Discovery of Pitolisant, the First Marketed Histamine H ₃ ‐Receptor Inverse Agonist/Antagonist for Treating Narcolepsy*

Structure‐Activity Relationship of Hetarylpropylguanidines Aiming at the Development of Selective Histamine Receptor Ligands^†

Structure‐Activity Relationship of Hetarylpropylguanidines Aiming at the Development of Selective Histamine Receptor Ligands^†

4-Oxypiperidine Ethers as Multiple Targeting Ligands at Histamine H₃ Receptors and Cholinesterases