Phenylalanine-Derived β-Lactam TRPM8 Modulators. Configuration Effect on the Antagonist Activity

Bonache, M. Ángeles; Llabrés, Pedro Juan; Martín-Escura, Cristina; Martínez, Rafael Giménez; Medina-Peris, Alicia; Butrón, Laura; Gómez-Monterrey, Isabel; Roa, Ana; Fernández‐Ballester, Gregorio; Ferrer-Montiel, Antonio; Fernández-Carvajal, Asia; González‐Muñiz, Rosario

doi:10.3390/ijms22052370

Cited by 2 publications

(3 citation statements)

References 56 publications

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“…Compound 40, and one of its isomers, exhibited micromolar non-selective antitumor activity in different tumor cell lines. Substitution of the benzyloxycarbonyl group in 40 by an N,N-dibenzyl moiety, and exploration of different configurations in these products, still provided improved antagonists, as published recently [169]. Compound 42 (Figure 6, Table 2), the most potent to date within this second generation of β-lactams, has nanomolar activity in both assays (IC 50 = 20 and 80 nM in Ca 2+ and Patch-Camp experiment, respectively).…”

Section: Trpm8 Antagonistsmentioning

confidence: 75%

TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation

Izquierdo

Martı́n-Martı́nez

Gómez-Monterrey

et al. 2021

IJMS

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The transient receptor potential melastatin subtype 8 (TRPM8) is a cold sensor in humans, activated by low temperatures (>10, <28 °C), but also a polymodal ion channel, stimulated by voltage, pressure, cooling compounds (menthol, icilin), and hyperosmolarity. An increased number of experimental results indicate the implication of TRPM8 channels in cold thermal transduction and pain detection, transmission, and maintenance in different tissues and organs. These channels also have a repercussion on different kinds of life-threatening tumors and other pathologies, which include urinary and respiratory tract dysfunctions, dry eye disease, and obesity. This compendium firstly covers newly described papers on the expression of TRPM8 channels and their correlation with pathological states. An overview on the structural knowledge, after cryo-electron microscopy success in solving different TRPM8 structures, as well as some insights obtained from mutagenesis studies, will follow. Most recently described families of TRPM8 modulators are also covered, along with a section of molecules that have reached clinical trials. To finalize, authors provide an outline of the potential prospects in the TRPM8 field.

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Section: Trpm8 Antagonistsmentioning

confidence: 75%

TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation

Izquierdo

Martı́n-Martı́nez

Gómez-Monterrey

et al. 2021

IJMS

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“…The resulting residue was purified on a silica gel column, using the eluent system indicated in each case. (34). Syrup.…”

Section: Synthesismentioning

confidence: 99%

“…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].…”

Section: Introductionmentioning

confidence: 99%

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

Martín-Escura,

Bonache,

Medina

et al. 2023

IJMS

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The protein transient receptor potential melastatin type 8 (TRPM8), a non-selective, calcium (Ca2+)-permeable ion channel is implicated in several pathological conditions, including neuropathic pain states. In our previous research endeavors, we have identified β-lactam derivatives with high hydrophobic character that exhibit potent and selective TRPM8 antagonist activity. This work describes the synthesis of novel derivatives featuring C-terminal amides and diversely substituted N′-terminal monobenzyl groups in an attempt to increase the total polar surface area (TPSA) in this family of compounds. The primary goal was to assess the influence of these substituents on the inhibition of menthol-induced cellular Ca2+ entry, thereby establishing critical structure–activity relationships. While the substitution of the tert-butyl ester by isobutyl amide moieties improved the antagonist activity, none of the N′-monobencyl derivatives, regardless of the substituent on the phenyl ring, achieved the activity of the model dibenzyl compound. The antagonist potency of the most effective compounds was subsequently verified using Patch-Clamp electrophysiology experiments. Furthermore, we evaluated the selectivity of one of these compounds against other members of the transient receptor potential (TRP) ion channel family and some receptors connected to peripheral pain pathways. This compound demonstrated specificity for TRPM8 channels. To better comprehend the potential mode of interaction, we conducted docking experiments to uncover plausible binding sites on the functionally active tetrameric protein. While the four main populated poses are located by the pore zone, a similar location to that described for the N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)-benzamide (AMTB) antagonist cannot be discarded. Finally, in vivo experiments, involving a couple of selected compounds, revealed significant antinociceptive activity within a mice model of cold allodynia induced by oxaliplatin (OXA).

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Phenylalanine-Derived β-Lactam TRPM8 Modulators. Configuration Effect on the Antagonist Activity

Cited by 2 publications

References 56 publications

TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation

TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation

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

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