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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.

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