Abstract
The diverse signaling pathways engaged by serotonin type 6 receptor (5-HT6R) together with its high constitutive activity suggests different types of pharmacological interventions for the treatment of CNS disorders. Non-physiological activation of mTOR kinase by constitutively active 5-HT6R under neuropathic pain conditions focused our attention on the possible repurposing of 5-HT6R inverse agonists as a strategy to treat painful symptoms associated with neuropathies of different etiologies. Herein, we report the identification of compound 33 derived from the library of 2-aryl-1H-pyrrole-3-carboxamides as a potential analgesic agent. Compound 33 behaves as a potent 5-HT6R inverse agonist at Gs, Cdk5, and mTOR signaling. Preliminary ADME/Tox studies revealed preferential distribution of 33 to the CNS and placed it in the low-risk safety space. Finally, compound 33 dose-dependently reduced tactile allodynia in spinal nerve ligation (SNL)-induced neuropathic rats.
Highlights
Neuropathic pain is a significant public health concern worldwide
We show that compound 33 inhibits agonistindependent 5-HT6R-operated activation of Gs, cyclin-dependent kinase 5 (Cdk5), and mechanistic target of rapamycin (mTOR) signaling, and that it reduces tactile allodynia in spinal nerve ligation (SNL)-induced neuropathic rats
A three-step synthesis was envisioned, consisting of BaylisHillman reaction of methylacrylate and heteroaryl aldehydes to provide alcohols 2j–k, which were subsequently converted into their corre sponding acetates 3j–k
Summary
Neuropathic pain is a significant public health concern worldwide. According to the International Association for the Study of Pain, 5–10% of adults are affected by chronic pain of neuropathic origin [1,2], resulting from a lesion or a disease affecting the central or peripheral somatosensory nervous system [3,4,5]. As an addition to a well-documented beneficial effect of 5-HT6R antagonists on cognition [15,16,17,18,19], recent studies have established that 5-HT6R blockade with SB-258585 or pyrazolo[3,4] pyridine-7-one and 1-aryl-5-isopropyl-pyrazole derivatives produces antiallodynic effect in neuropathic rats [20,21,22]. We have recently demonstrated that these effects might result from blockade of mTOR activation by constitutively active spinal 5-HT6Rs [10] These observations are consistent with studies that identified mTOR kinase as a crucial regulator of central and peripheral pain sensitization [23,24] and demonstrated that its inhibi tion by rapamycin produces analgesic effects in a wide range of painrelated paradigms in rodents [25,26,27]. We show that compound 33 inhibits agonistindependent 5-HT6R-operated activation of Gs, Cdk, and mTOR signaling, and that it reduces tactile allodynia in spinal nerve ligation (SNL)-induced neuropathic rats
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