RESUMEN
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 ß-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 Ca2+ microfluorometry assay, and confirmed electrophysiologically for the best enantiopure ß-lactams 24a and 29a (IC50, 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 ß-lactams and KPs. ß-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.
Asunto(s)
Analgésicos/uso terapéutico , Antineoplásicos/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Piperazinas/uso terapéutico , Canales Catiónicos TRPM/antagonistas & inhibidores , beta-Lactamas/uso terapéutico , Analgésicos/síntesis química , Analgésicos/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Línea Celular Tumoral , Frío/efectos adversos , Simulación por Computador , Citofotometría , Evaluación Preclínica de Medicamentos , Masculino , Ratones , Modelos Moleculares , Simulación del Acoplamiento Molecular , Estructura Molecular , Oxaliplatino/toxicidad , Técnicas de Placa-Clamp , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Piperazinas/síntesis química , Piperazinas/farmacología , Relación Estructura-Actividad , beta-Lactamas/síntesis química , beta-Lactamas/farmacologíaRESUMEN
High-throughput screening of an array of biphenylmethylamines synthesised by high-throughput solid-phase chemistry resulted in the identification of compounds with high-affinity for the 5-ht5A receptor. The structure-activity relationship within this series and further array synthesis led to the identification of the biphenylmethylamine derivative 11, a potent and selective 5-ht5A receptor antagonist.