Structure-Based Design of Novel Biphenyl Amide Antagonists of Human Transient Receptor Potential Cation Channel Subfamily M Member 8 Channels with Potential Implications in the Treatment of Sensory Neuropathies

Journigan, V. Blair; Feng, Zhiwei; Rahman, S.M. Jamshedur; Wang, Yuanqiang; Amin, A.R.M. Ruhul; Heffner, Colleen E.; Bachtel, Nicholas; Wang, Siyi; González-Rodríguez, Sara; Fernández-Carvajal, Asia; Fernández‐Ballester, Gregorio; Hilton, Jacob; Horn, Wade D. Van; Ferrer-Montiel, Antonio; Xie, Xiang‐Qun; Rahman, Taufiq

doi:10.1021/acschemneuro.9b00404

Cited by 17 publications

(48 citation statements)

References 112 publications

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“…Thus, its potency is higher than that of a described spirochromene derivative 59 , and seems to span longer than that of a Trp-OMe derivative, which showed more potent antagonist activity at the Ca 2+ assay than 24a 34 . At 1 µg i.pl., β-lactam derivative 24a showed slightly lower potency and similar duration of action than a biphenyl amide TRPM8 antagonist recently reported 60 .…”

Section: Discussionmentioning

confidence: 65%

Highly functionalized β-lactams and 2-ketopiperazines as TRPM8 antagonists with antiallodynic activity

Bonache

Martín-Escura

Martínez

et al. 2020

Sci Rep

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The cool sensor transient receptor potential melastatin channel 8 (TRPM8) is highly expressed in trigeminal and dorsal root ganglia, playing a key role in cold hypersensitivity associated to different peripheral neuropathies. Moreover, these channels are aberrantly expressed in different cancers, and seem to participate in tumor progression, survival and invasion. Accordingly, the search for potent and selective TRPM8 modulators attracted great interest in recent years. We describe new heterocyclic TRPM8 antagonist chemotypes derived from N-cloroalkyl phenylalaninol-Phe conjugates. The cyclization of these conjugates afforded highly substituted β-lactams and/or 2-ketopiperazine (KP) derivatives, with regioselectivity depending on the N-chloroalkyl group and the configuration. These derivatives behave as TRPM8 antagonists in the Ca 2+ microfluorometry assay, and confirmed electrophysiologically for the best enantiopure β-lactams 24a and 29a (IC 50 , 1.4 and 0.8 µM). Two putative binding sites by the pore zone, different from those found for typical agonists and antagonists, were identified by in silico studies for both β-lactams and KPs. β-Lactams 24a and 29a display antitumor activity in different human tumor cell lines (micromolar potencies, A549, HT29, PSN1), but correlation with TRPM8 expression could not be established. Additionally, compound 24a significantly reduced cold allodynia in a mice model of oxaliplatin-induced peripheral neuropathy.

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Section: Discussionmentioning

confidence: 65%

Highly functionalized β-lactams and 2-ketopiperazines as TRPM8 antagonists with antiallodynic activity

Bonache

Martín-Escura

Martínez

et al. 2020

Sci Rep

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“…Menthol acts as an agonist of TRPM8 and a NAM of α4β2 nAChRs [ 35 ]. This novel series of compounds were characterized as antagonists of TRPM8 [ 25 ] , and we found they failed to stimulate α4β2 nAChR activation on their own. However, they increased nAChR function in a concentration-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

“…We utilized a nicotine dose of 0.5 mg/kg (with respect to free base) for its previously determined rewarding effect for mice in conditioned place preference assays [ 19 , 29 ]. VBJ series compounds (see Table 1 ) were prepared as described previously [ 25 ]. All molecules were >99.6% pure, as determined by elemental analysis.…”

Section: Methodsmentioning

confidence: 99%

“…Given that menthol is a well-characterized agonist of TRPM8, some have speculated that TRPM8 antagonists may be potential candidates as novel pharmacotherapies for smoking cessation, by directly affecting nicotinic pharmacology or by blocking menthol’s counter-irritant effects in relation to smoke inhalation. A novel class of menthol-derived TRPM8 antagonists has recently been discovered [ 25 ]. Based on menthol’s ability to enhance nicotine reward-related behavior, we tested these novel TRPM8 antagonists for their ability to modulate nicotine reward-related behavior using a mouse model of conditioned place preference.…”

Section: Introductionmentioning

confidence: 99%

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Novel Putative Positive Modulators of α4β2 nAChRs Potentiate Nicotine Reward-Related Behavior

et al. 2021

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The popular tobacco and e-cigarette chemical flavorant (−)-menthol acts as a nonselective, noncompetitive antagonist of nicotinic acetylcholine receptors (nAChRs), and contributes to multiple physiological effects that exacerbates nicotine addiction-related behavior. Menthol is classically known as a TRPM8 agonist; therefore, some have postulated that TRPM8 antagonists may be potential candidates for novel nicotine cessation pharmacotherapies. Here, we examine a novel class of TRPM8 antagonists for their ability to alter nicotine reward-related behavior in a mouse model of conditioned place preference. We found that these novel ligands enhanced nicotine reward-related behavior in a mouse model of conditioned place preference. To gain an understanding of the potential mechanism, we examined these ligands on mouse α4β2 nAChRs transiently transfected into neuroblastoma-2a cells. Using calcium flux assays, we determined that these ligands act as positive modulators (PMs) on α4β2 nAChRs. Due to α4β2 nAChRs’ important role in nicotine dependence, as well as various neurological disorders including Parkinson’s disease, the identification of these ligands as α4β2 nAChR PMs is an important finding, and they may serve as novel molecular tools for future nAChR-related investigations.

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“…Among described TRPM8 agonists, we mainly found tertiary amides and diverse menthol derivatives [ 26 , 27 , 28 ], and some other natural products [ 29 ]. The family of TRPM8 antagonists is highly diverse, with either different acyclic (amide, sulfonamide, urea, glycine, tryptophan) or heterocyclic (tiazole, 2-azetidinone, benzothiophene, benzimidazole, isoquinoline) central scaffolds [ 27 , 28 , 30 , 31 , 32 , 33 , 34 ]. Despite the big number of TRPM8 modulators described to date, only a few have been extended to clinical studies, with the exception of menthol that has been profusely scrutinized as a topical antihyperalgesic agent.…”

Section: Introductionmentioning

confidence: 99%

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

Bonache

Llabrés

Martín-Escura

et al. 2021

IJMS

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Transient receptor potential cation channel subfamily M member 8 (TRPM8) is a Ca2+ non-selective ion channel implicated in a variety of pathological conditions, including cancer, inflammatory and neuropathic pain. In previous works we identified a family of chiral, highly hydrophobic β–lactam derivatives, and began to intuit a possible effect of the stereogenic centers on the antagonist activity. To investigate the influence of configuration on the TRPM8 antagonist properties, here we prepare and characterize four possible diastereoisomeric derivatives of 4-benzyl-1-[(3’-phenyl-2’-dibenzylamino)prop-1’-yl]-4-benzyloxycarbonyl-3-methyl-2-oxoazetidine. In microfluorography assays, all isomers were able to reduce the menthol-induced cell Ca2+ entry to larger or lesser extent. Potency follows the order 3R,4R,2’R > 3S,4S,2’R ≅ 3R,4R,2’S > 3S,4S,2’S, with the most potent diastereoisomer showing a half inhibitory concentration (IC50) in the low nanomolar range, confirmed by Patch-Clamp electrophysiology experiments. All four compounds display high receptor selectivity against other members of the TRP family. Furthermore, in primary cultures of rat dorsal root ganglion (DRG) neurons, the most potent diastereoisomers do not produce any alteration in neuronal excitability, indicating their high specificity for TRPM8 channels. Docking studies positioned these β-lactams at different subsites by the pore zone, suggesting a different mechanism than the known N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)-benzamide (AMTB) antagonist.

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Structure-Based Design of Novel Biphenyl Amide Antagonists of Human Transient Receptor Potential Cation Channel Subfamily M Member 8 Channels with Potential Implications in the Treatment of Sensory Neuropathies

Cited by 17 publications

References 112 publications

Highly functionalized β-lactams and 2-ketopiperazines as TRPM8 antagonists with antiallodynic activity

Highly functionalized β-lactams and 2-ketopiperazines as TRPM8 antagonists with antiallodynic activity

Novel Putative Positive Modulators of α4β2 nAChRs Potentiate Nicotine Reward-Related Behavior

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

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