Neuropathic pain-alleviating activity of novel 5-HT6 receptor inverse agonists derived from 2-aryl-1H-pyrrole-3-carboxamide

Drop, Marcin; Jacquot, Florian; Canale, Vittorio; Chaumont‐Dubel, Séverine; Walczak, Maria; Satała, Grzegorz; Nosalska, Klaudia; Mahoro, Gilbert Umuhire; Słoczyńska, Karolina; Piska, Kamil; Lamoine, Sylvain; Pękala, Elżbieta; Masurier, Nicolas; Bojarski, Andrzej J.; Pawłowski, Maciej; Martínez, Jean; Subra, Gilles; Bantreil, Xavier; Eschalier, Alain; Marin, Philippe; Courteix, Christine; Zajdel, Paweł

doi:10.1016/j.bioorg.2021.105218

Cited by 6 publications

(11 citation statements)

References 52 publications

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“…The initial demonstration of in vivo constitutive activity of 5-HT 6 receptors in preclinical models of traumatic (spinal nerve ligation) and toxic (oxaliplatin injection) neuropathic pain was conducted with the demonstration of concomitant activation of mTOR signaling by constitutively active 5-HT 6 receptors [52]. Recently, 5-HT 6 receptor inverse agonists [53,54], including SB258585 (first described as a neutral antagonist [55], and also rapamycin (mTOR inhibitor), was shown to reverse mechanical hyperalgesia and reduce cognitive co-morbidities in STZ diabetic rats, demonstrating the role of the constitutive activity of 5-HT 6 receptors in diabetic neuropathic pain and associated cognitive deficits and that of mTOR activation by constitutively active 5-HT 6 receptors [56]. In this study, the intrathecal administration of a cell-penetrating mimetic peptide that disrupts the physical interaction between the 10 amino-acyl residues of the C-terminus of the 5-HT 6 receptor and mTOR protein [52], also suppressed mechanical hyperalgesia in STZ diabetic rats [56].…”

Section: Effect Of Compounds Acting On 5-ht 6 Receptorsmentioning

confidence: 99%

Diabetic Neuropathic Pain and Serotonin: What Is New in the Last 15 Years?

2023

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The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) is involved in numerous physiological functions and plays a key role in pain modulation including neuropathic pain. Diabetic neuropathy is a common complication of diabetes mellitus often accompanied by chronic neuropathic pain. Animal models of diabetes offer relevant tools for studying the pathophysiological mechanisms and pharmacological sensitivity of diabetic neuropathic pain and for identifying new therapeutic targets. In this review, we report data from preclinical work published over the last 15 years on the analgesic activity of drugs acting on the serotonergic system, such as serotonin and noradrenaline reuptake inhibitor (SNRI) antidepressants, and on the involvement of certain serotonin receptors-in particular 5-HT1A, 5-HT2A/2c and 5-HT6 receptors-in rodent models of painful diabetic neuropathy.

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Section: Effect Of Compounds Acting On 5-ht 6 Receptorsmentioning

confidence: 99%

Diabetic Neuropathic Pain and Serotonin: What Is New in the Last 15 Years?

2023

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“…The ability of compounds 3e, 3f, and 3g to inhibit 5-CT-induced production of cAMP was assessed using 1321N1 cells expressing the human 5-HT 6 R (PerkinElmer) using previously described procedures [15,17]. The level of cAMP was measured using the LANCE cAMP detection kit (PerkinElmer) according to the manufacturer's protocol.…”

Section: Impact Of Evaluated Compounds On Camp Production In 1321n1 C...mentioning

confidence: 99%

“…An important feature of the 5-HT 6 R is its high level of ligand-independent constitutive activity, which corresponds to the ability of a receptor to be active even in the absence of an agonist [10]. The role of 5-HT 6 R constitutive activity at canonical Gs signaling and non-canonical signaling has been described in various pathophysiological conditions [11][12][13][14][15]. Consistent with those findings, the development of 5-HT 6 R ligands acting as inverse agonists and/or neutral antagonists at the different 5-HT 6 R-operated signaling pathways is of utmost interest to decipher the cellular mechanism(s) under the control of the various 5-HT 6 R signal transduction mechanisms and of constitutive vs. agonist-dependent receptor activation.…”

Section: Introductionmentioning

confidence: 99%

1-(Arylsulfonyl-isoindol-2-yl)piperazines as 5-HT6R Antagonists: Mechanochemical Synthesis, In Vitro Pharmacological Properties and Glioprotective Activity

et al. 2022

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In addition to the canonical Gs adenylyl cyclase pathway, the serotonin type 6 receptor (5-HT6R) recruits additional signaling pathways that control cognitive function, brain development, and synaptic plasticity in an agonist-dependent and independent manner. Considering that aberrant constitutive and agonist-induced active states are involved in various pathological mechanisms, the development of biased ligands with different functional profiles at specific 5-HT6R-elicited signaling pathways may provide a novel therapeutic perspective in the field of neurodegenerative and psychiatric diseases. Based on the structure of SB-258585, an inverse agonist at 5-HT6R-operated Gs and Cdk5 signaling, we designed a series of 1-(arylsulfonyl-isoindol-2-yl)piperazine derivatives and synthesized them using a sustainable mechanochemical method. We identified the safe and metabolically stable biased ligand 3g, which behaves as a neutral antagonist at the 5-HT6R-operated Gs signaling and displays inverse agonist activity at the Cdk5 pathway. Inversion of the sulfonamide bond combined with its incorporation into the isoindoline scaffold switched the functional profile of 3g at Gs signaling with no impact at the Cdk5 pathway. Compound 3g reduced the cytotoxicity of 6-OHDA and produced a glioprotective effect against rotenone-induced toxicity in C8-D1A astrocyte cell cultures. In view of these findings, compound 3g can be considered a promising biased ligand to investigate the role of the 5-HT6R-elicited Gs and Cdk5 signaling pathways in neurodegenerative diseases.

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“…Preclinical studies performed in animal models of neuropathic pain resembling human neuropathic pain with a high translational value have shown that 5-HT 6 receptor ligands have a strong analgesic potential and may be new candidates to treat traumatic and chemotherapy-induced peripheral neuropathy (CIPN) [21,22]. The mechanism of action of such ligands relies on their ability to abolish the constitutive activity, serotonin independent, of 5-HT 6 receptors, abnormally enhanced in these pathological situations.…”

Section: Introductionmentioning

confidence: 99%

“…The drugs acting as inverse agonists were shown to inhibit the mechanistic target of rapamycin (mTOR) signaling upon 5-HT 6 receptor dependence in the dorsal horn spinal cord, whereas 5-HT 6 receptor-neutral antagonists failed to inhibit mTOR activity and alleviate neuropathic pain [21]. PZ-1386 and PZ-1179 belong to a class of 2-phenyl-1H-pyrrole-3-carboxamides and behave as inverse agonists of 5-HT 6 receptor with Ki values of 23 nM and 30 nM, respectively [22,23]. Pharmacokinetic studies revealed that both compounds could pass through the blood-brain barrier reaching Cmax in the brain after 30 min (PZ-1386) and 5 min (PZ-1179).…”

Section: Introductionmentioning

confidence: 99%

The Constitutive Activity of Spinal 5-HT6 Receptors Contributes to Diabetic Neuropathic Pain in Rats

et al. 2023

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Diabetic neuropathy is often associated with chronic pain. Serotonin type 6 (5-HT6) receptor ligands, particularly inverse agonists, have strong analgesic potential and may be new candidates for treating diabetic neuropathic pain and associated co-morbid cognitive deficits. The current study addressed the involvement of 5-HT6 receptor constitutive activity and mTOR signaling in an experimental model of diabetic neuropathic pain induced by streptozocin (STZ) injection in the rat. Here, we show that mechanical hyperalgesia and associated cognitive deficits are suppressed by the administration of 5-HT6 receptor inverse agonists or rapamycin. The 5-HT6 receptor ligands also reduced tactile allodynia in traumatic and toxic neuropathic pain induced by spinal nerve ligation and oxaliplatin injection. Furthermore, both painful and co-morbid cognitive symptoms in diabetic rats are reduced by intrathecal delivery of a cell-penetrating peptide that disrupts 5-HT6 receptor-mTOR physical interaction. These findings demonstrate the deleterious influence of the constitutive activity of spinal 5-HT6 receptors upon painful and cognitive symptoms in diabetic neuropathic pains of different etiologies. They suggest that targeting the constitutive activity of 5-HT6 receptors with inverse agonists or disrupting the 5-HT6 receptor-mTOR interaction might be valuable strategies for the alleviation of diabetic neuropathic pain and cognitive co-morbidities.

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Neuropathic pain-alleviating activity of novel 5-HT6 receptor inverse agonists derived from 2-aryl-1H-pyrrole-3-carboxamide

Cited by 6 publications

References 52 publications

Diabetic Neuropathic Pain and Serotonin: What Is New in the Last 15 Years?

Diabetic Neuropathic Pain and Serotonin: What Is New in the Last 15 Years?

1-(Arylsulfonyl-isoindol-2-yl)piperazines as 5-HT6R Antagonists: Mechanochemical Synthesis, In Vitro Pharmacological Properties and Glioprotective Activity

The Constitutive Activity of Spinal 5-HT6 Receptors Contributes to Diabetic Neuropathic Pain in Rats

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