β–Lactam TRPM8 Antagonist RGM8-51 Displays Antinociceptive Activity in Different Animal Models

Abstract

Transient receptor potential melastatin subtype 8 (TRPM8) is a cation channel extensively expressed in sensory neurons and implicated in different painful states. However, the effectiveness of TRPM8 modulators for pain relief is still a matter of discussion, since structurally diverse modulators lead to different results, depending on the animal pain model. In this work, we described the antinociceptive activity of a β–lactam derivative, RGM8-51, showing good TRPM8 antagonist activity, and selectivity against related thermoTRP channels and other pain-mediating receptors. In primary cultures of rat dorsal root ganglion (DRG) neurons, RGM8-51 potently reduced menthol-evoked neuronal firing without affecting the major ion conductances responsible for action potential generation. This compound has in vivo antinociceptive activity in response to cold, in a mouse model of oxaliplatin-induced peripheral neuropathy. In addition, it reduces cold, mechanical and heat hypersensitivity in a rat model of neuropathic pain arising after chronic constriction of the sciatic nerve. Furthermore, RGM8-51 exhibits mechanical hypersensitivity-relieving activity, in a mouse model of NTG-induced hyperesthesia. Taken together, these preclinical results substantiate that this TRPM8 antagonist is a promising pharmacological tool to study TRPM8-related diseases.

β-Lactam TRPM8 Antagonists Derived from Phe-Phenylalaninol Conjugates: Structure–Activity Relationships and Antiallodynic Activity

“…As outlined in Table 5, it is evident that compound 34 did not exhibit noteworthy modulatory effects on any of the assessed TRP and ASIC3 channels. Importantly, amide derivative 34 did not show activation on the TRPV1 channel, which was about 30% in the model compound 1 [35]. Compound 35 underwent evaluation as a potential antagonist for the TRPM3 channel, revealing a non-significant degree of inhibition (4.1 ± 10.8) in the Ca 2+ influx induced by pregnenolone sulfate.…”

“…In this newly designed series, the most promising substituents identified earlier were incorporated onto a 1,3,4,4-tetrasubstituted β-lactam scaffold. These enantiopure β-lactams can be synthesized using chiral 2-chloropropanoic acid derivatives as previously reported [35,39].…”

“…In previous research, our team has identified several β-lactam derivatives exhibiting potent and selective TRPM8 antagonist activity [33,34]. Furthermore, some of these derivatives have demonstrated antinociceptive properties in various animal models [35]. In the present study, our focus lies on deepening our understanding of the structure-activity relationships within this compound family.…”

“…As TRPM8 mediated the permeation of large cations across cell membranes [56], and both AMTB and our β-lactamas are cationic molecules, the preferential situation of these molecules by the pore hole could be plausible. To investigate whether the extracellular loops in the previous model play a role in guiding the distribution of β-lactam derivatives into cavities along the pore zone, as previously hypothesized for related analogs [35], an additional structure of the channel was incorporated into the modeling studies (compounds 34 and 37). This alternate structure retained the transmembrane helices and inner pore loops but excluded the extracellular loops.…”

“…1 H-NMR (400 MHz, CDCl 3 ): δ 7.75-6.89 (m, 20H, Ar), 6.08 (t, J = 6.5 Hz, 1H, NH), 3.72 (s, 4H, NCH 2 ), 3.72 (dd, J = 14.3, 6.7 Hz, 1H, H 1 ), 3.25 (p, J = 6.9 Hz, 1H, H 2 ), 3.18 (dd, J = 14.3, 3.8 Hz, 1H, H 1 ), 3.16 (d, J = 14.5 Hz, 1H, 4-CH 2 ), 3.16 (m, 1H, H 3 ), 3.02 (d, J = 14.6 Hz, 1H, 4-CH 2 ), 2.95 (dd, J = 13.3, 6.7 Hz, 1H, CH 2 , i Bu), 2.84 (dd, J = 13.8, 6.6 Hz, 1H, H 3 ), 2.82 (dd, J = 13.4, 6.6 Hz, 1H, CH 2 , i Bu), 2.61 (dd, J = 13.8, 7.1 Hz, 1H, H 3 ), 1.46 (m, 1H, CH, i Bu), 1.18 (d, J = 7.5 Hz, 3H, 3-CH 3 ), 0.75 (d, J = 6.7 Hz, 3H, CH 3 , i Bu), 0.71 (d, J = 6.7 Hz, 3H, CH 3 , i Bu). 13 (35). Syrup.…”