Identification of a Potent Tryptophan-Based TRPM8 Antagonist With in Vivo Analgesic Activity

TRPM8
has been implicated in nociception and pain and is currently
regarded as an attractive target for the pharmacological treatment
of neuropathic pain syndromes. A series of analogues of N,N′-dibenzyl tryptamine 1, a
potent TRPM8 antagonist, was prepared and screened using a fluorescence-based
in vitro assay based on menthol-evoked calcium influx in TRPM8 stably
transfected HEK293 cells. The tryptophan derivative 14 was identified as a potent (IC50 0.2 ± 0.2 nM) and
selective TRPM8 antagonist. In vivo, 14 showed significant
target coverage in both an icilin-induced WDS (at 1–30 mg/kg
s.c.) and oxaliplatin-induced cold allodynia (at 0.1–1 μg
s.c.) mice models. Molecular modeling studies identified the putative
binding mode of these antagonists, suggesting that they could influence
an interaction network between the S1–4 transmembrane segments
and the TRP domains of the channel subunits. The tryptophan moiety
provides a new pharmacophoric scaffold for the design of highly potent
modulators of TRPM8-mediated pain.