Abstract
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.
Highlights
TRPM8 is a cold-sensing multimodal nociceptor of the somatosensory nervous system and a major sensor of cold nociception in humans [7,8]. They are highly expressed in primary sensory neurons (Aδ and C-fibers) of the dorsal root ganglia (DRG) and trigeminal ganglia (TG) [9], which participate in the sensory encoding of pain under both normal and pathological conditions
Sci. 2021, 22, 2370those obtained for the corresponding 2′-benzyloxycarbonyl derivatives [41], but some hydrolysis of the benzyl ester was observed during the cyclization step workup
In our series of β–lactam TRPM8 antagonists we have mainly studied all S
Summary
Transient receptor potential cation channel subfamily M member 8 (TRPM8), is a calcium-permeable ion channel, activated by innocuous cooling to cold temperatures (below 28 ◦ C), membrane depolarization, changes in osmolarity and pH [1,2]. It is activated by chemical agents such as (−)-menthol and icilin, and by different endogenous molecules, such as the lipid PIP2 [3], testosterone [4], artemin [5] and Pirt (phosphoinositide interacting regulator of TRPs) [6]. Docking studies indicated that compound 1 localizes preferentially at two possible locations by the pore zone of the TRPM8 channel, suggesting either an allosteric or a pore blocking mechanism, different to that of other described antagonists
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