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Synthesis, high-throughput screening and pharmacological characterization of ?-lactam derivatives as TRPM8 antagonists.

ABSTRACT: The mammalian transient receptor potential melastatin channel 8 (TRPM8), highly expressed in trigeminal and dorsal root ganglia, mediates the cooling sensation and plays an important role in the cold hypersensitivity characteristic of some types of neuropathic pain, as well as in cancer. Consequently, the identification of selective and potent ligands for TRPM8 is of great interest. Here, a series of compounds, having a ?-lactam central scaffold, were prepared to explore the pharmacophore requirements for TRPM8 modulation. Structure-activity studies indicate that the minimal requirements for potent ?-lactam-based TRPM8 blockers are hydrophobic groups (benzyl preferentially or t Bu) on R1, R2, R3 and R5 and a short N-alkyl chain (?3 carbons). The best compounds in the focused library (41 and 45) showed IC50 values of 46 nM and 83 nM, respectively, in electrophysiology assays. These compounds selectively blocked all modalities of TRPM8 activation, i.e. menthol, voltage, and temperature. Molecular modelling studies using a homology model of TRPM8 identified two putative binding sites, involving networks of hydrophobic interactions, and suggesting a negative allosteric modulation through the stabilization of the closed state. Thus, these ?-lactams provide a novel pharmacophore scaffold to evolve TRPM8 allosteric modulators to treat TRPM8 channel dysfunction.

SUBMITTER: de la Torre-Martinez R

PROVIDER: S-EPMC5589751 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Synthesis, high-throughput screening and pharmacological characterization of β-lactam derivatives as TRPM8 antagonists.

de la Torre-Martínez Roberto R Bonache M Angeles MA Llabrés-Campaner Pedro J PJ Balsera Beatriz B Fernández-Carvajal Asia A Fernández-Ballester Gregorio G Ferrer-Montiel Antonio A Pérez de Vega M Jesús MJ González-Muñiz Rosario R

Scientific reports 20170907 1

The mammalian transient receptor potential melastatin channel 8 (TRPM8), highly expressed in trigeminal and dorsal root ganglia, mediates the cooling sensation and plays an important role in the cold hypersensitivity characteristic of some types of neuropathic pain, as well as in cancer. Consequently, the identification of selective and potent ligands for TRPM8 is of great interest. Here, a series of compounds, having a β-lactam central scaffold, were prepared to explore the pharmacophore requir ...[more]

PMID: 28883526

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Project description: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).

Dataset Information

Synthesis, high-throughput screening and pharmacological characterization of ?-lactam derivatives as TRPM8 antagonists.

Publications

Synthesis, high-throughput screening and pharmacological characterization of β-lactam derivatives as TRPM8 antagonists.

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