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

Abstract

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 diferent peripheral neuropathies. Moreover, these channels are aberrantly expressed in diferent cancers, and seem to participate in tumor progression, survival and invasion.Accordingly, the search for potent and selectiveTRPM8 modulators attracted great interest in recent years.We describe new heterocyclicTRPM8 antagonist chemotypes derived from N-cloroalkyl phenylalaninol-Phe conjugates. The cyclization of these conjugates aforded highly substituted β-lactams and/or 2-ketopiperazine (KP) derivatives, with regioselectivity depending on the N-chloroalkyl group and the confguration. These derivatives behave asTRPM8 antagonists in the ­Ca2+ microfuorometry assay, and confrmed electrophysiologically for the best enantiopure β-lactams 24a and 29a ­(IC50, 1.4 and 0.8 µM). Two putative binding sites by the pore zone, diferent from those found for typical agonists and antagonists, were identifed by in silico studies for both β-lactams and KPs. β-Lactams 24a and 29a display antitumor activity in diferent human tumor cell lines (micromolar potencies,A549, HT29, PSN1), but correlation withTRPM8 expression could not be established.Additionally, compound 24a signifcantly reduced cold allodynia in a mice model of oxaliplatin-induced peripheral neuropathy.