Tryptamine-Based Derivatives as Transient Receptor Potential Melastatin Type 8 (TRPM8) Channel Modulators

Pharmacological modulation of the
transient receptor potential
melastatin type 8 (TRPM8) is currently under investigation as a new
approach for the treatment of pain and other diseases. In this study,
a series of N-substituted tryptamines was prepared to explore the
structural requirements determining TRPM8 modulation. Using a fluorescence-based
screening assay, we identified two compounds acting as an activator
(2-(1H-indol-3-yl)-N-(4-phenoxybenzyl)­ethanamine, 21) or an inhibitor (N,N-dibenzyl-2-(1H-indol-3-yl)­ethanamine, 12) of calcium influx in HEK293 cells. In patch-clamp recordings, compound 21 displayed a significantly higher potency (EC50 = 40 ± 4 μM) and a similar efficacy when compared to
menthol; by contrast, compound 12 produced a concentration-dependent
inhibition of menthol-induced TRPM8 currents (IC50 = 367
± 24 nM). Molecular modeling studies using a homology model of
a single rat TRPM8 subunit identified a putative binding site located
between the VSD and the TRP box, disclosing differences in the binding
modes for the agonist and the antagonist.