Discovery of RC-752, a Novel Sigma-1 Receptor Antagonist with Antinociceptive Activity: A Promising Tool for Fighting Neuropathic Pain

Abstract

Neuropathic pain (NP) is a chronic condition resulting from damaged pain-signaling pathways. It is a debilitating disorder that affects up to 10% of the world’s population. Although opioid analgesics are effective in reducing pain, they present severe risks; so, there is a pressing need for non-opioid pain-relieving drugs. One potential alternative is represented by sigma-1 receptor (S1R) antagonists due to their promising analgesic effects. Here, we report the synthesis and biological evaluation of a series of S1R antagonists based on a 2-aryl-4-aminobutanol scaffold. After assessing affinity toward the S1R and selectivity over the sigma-2 receptor (S2R), we evaluated the agonist/antagonist profile of the compounds by investigating their effects on nerve growth factor-induced neurite outgrowth and aquaporin-mediated water permeability in the presence and absence of oxidative stress. (R/S)-RC-752 emerged as the most interesting compound for S1R affinity (Ki S1R = 6.2 ± 0.9) and functional antagonist activity. Furthermore, it showed no cytotoxic effect in two normal human cell lines or in an in vivo zebrafish model and was stable after incubation in mouse plasma. (R/S)-RC-752 was then evaluated in two animal models of NP: the formalin test and the spinal nerve ligation model. The results clearly demonstrated that compound (R/S)-RC-752 effectively alleviated pain in both animal models, thus providing the proof of concept of its efficacy as an antinociceptive agent.

A green Heck reaction protocol towards trisubstituted alkenes, versatile pharmaceutical intermediates

“…Compound 11 is another product of interest for our medicinal chemistry projects, as it is an intermediate of RC-33 and RC-752, other in-house developed Sigma Receptor modulators. Also, in this case, the yield is superimposable to that obtained in our previous works using DMF, conventional heating, and long reaction times ( Rossino et al, 2021 , 2023 ). Exceptions include phenyls with electron-donating groups in the para position (i.e., compounds 7 and 8 ), probably due to the strengthening effect of the substituent toward the C-Br bond.…”

“…The reaction was initially performed under “conventional” conditions ( Table 1 , entry 1), following a protocol already reported by us ( Listro et al, 2020 ; Rossino et al, 2023 ). The catalyst was Pd EnCat ® 40 (0.4 mmol/g Pd loading), a commercial catalyst constituted by palladium acetate microencapsulated in a polyurea matrix ( Ley et al, 2002 ; Ramarao et al, 2002 ; Pd EnCat, 2022 ).…”

“…RC-106, our in-house developed pan-sigma modulator, has promising anticancer activity ( Tesei et al, 2019 ; Cortesi et al, 2020 ). On the other hand, the double bond can be reduced to switch to a selective S1R modulation, thus promoting neuroprotective or antinociceptive effects (as in the case of RC-33 and RC-752, respectively) ( Marra et al, 2016 ; Rossino et al, 2023 ). Therefore, we focused on greening the synthesis of compounds with general scaffold A , using the synthesis of E - 1 ( Scheme 1 ) as a model reaction.…”