Isoxazole derivatives as potent transient receptor potential melastatin type 8 (TRPM8) agonists

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

“…The non-substituted N-1 indole derivatives (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21) were quite productive. A direct linkage of the amine moiety with different bulky aromatic groups, such as naphthalene and quinolines, gives compounds 8-11 unable to act as TRPM8 modulators ( Figures 1A and 1B).…”

“…28 Reductive amination of different commercially available aldehydes with the tryptamine, using sodium triacetoxyborohydride as reductive agent gave the final compounds 15-21 in 51% -85% yields (Scheme 2). 21 Finally, treatment of derivative 21 with methyl iodide using NaH as a base allowed us to obtained the dimethyl derivative 22 in 37% yield. Scheme 2.…”

“…Conversion of this compound to its N-methyl-2-(1-methyl-1H-indol-3-yl)-derivative (22) shifted the agonistic activity to antagonism, with an efficacy comparable to that of derivative 12, at all tested concentrations ( Figure 1B). To investigate the ability of newly-described TRPM8 modulators to interfere with the activity of other TRP channels, particularly TRPV1 and TRPA1, two TRPM8 antagonist (12,22) and one agonist (21), were also tested in calcium fluorometric experiments in SH-SY5Y cells stably expressing mouse TRPV1 channels and in IMR90 cells natively expressing mouse TRPA1 channels. In this experiment the canonical TRPV1 agonist (capsaicin, 10 M) or antagonist (ruthenium red, 10 M) as well as the canonical TRPA1 agonist (AITC, 500 M) or antagonist (ruthenium red, 10 M) were used as controls.…”

“…26 In addition, in a previous work we demonstrated that the potency of TRPM8 ligands could be modulated varying substituents on the nitrogen group of the aminoisoxazole scaffold. 21 On the basis of these findings, we synthesized a focused library of 18 tryptamine-based compounds and tested their activity as TRPM8 modulators by performing a fluorescence-based assay and patch-clamp recordings. Pharmacological activity was rationalized by molecular modelling studies defining basic structural requirements for TRPM8 agonism and antagonism.…”

“…13,14 For these reasons, increasing efforts have been dedicated, both by academia and industry, to the design of TRPM8 ligands starting from different structural scaffolds. [15][16][17][18][19][20][21][22] Most of the compounds described in the literature showed high potency on TRPM8 channels, although they also show agonistic and/or antagonistic properties towards other TRP receptors, such as TRPA1 and TRPV1 channels. 23,24 Recently, some indole alkaloids have been identified, 25 resulting in potent antagonists with a pronounced selectivity for TRPM8 when compared to TRPA1 or TRPV1 channels.…”