Transient receptor potential melastatin type-8 (TRPM8), is a transmembrane, non selective Ca2+ permeable cation channel. Despite this channel is mainly considered as the major sensor for peripheral innocuous cool, its modulation is responsible for several physiopathological processes. In fact, TRPM8 antagonists have been reported to induce strong analgesia [1], whereas the same effect has been described when agonists are administered in a in a range of very low concentrations [2]. TRPM8 agonists have been also proposed as useful diagnostic and therapeutic tools for the treatment of prostate cancer and benign prostate hyperplasia (BPH) [3], while antagonists have been investigated for the treatment of overactive and painful bladder syndromes [4]. Thus, increasing efforts in the last few years have been dedicated to the design of selective and potent TRPM8 ligands. Starting from these evidence, the aim of the present study has been to synthesize and evaluate the biological activity of a small library of N-substituted tryptamines (Figure 1) as TRPM8 modulators. These derivatives were preliminary screened for their activity and selectivity among TRP channels by in vitro Ca2+-imaging experiments using Fluo4-NW in cells stably expressing TRPM8 (HEK), TRPV1 (SH-SY5Y ) or TRPA1 (IMR90) channels. The most active molecules were further investigated by electrophysiological recordings in HEK cells transiently expressing TRPM8 channels. One rather potent agonist (IGM01-5, EC50= 40±3 μM) and one antagonist (IGM01-18, IC50=367±24 nM) of TRPM8 channels were identified. These derivatives failed to show functional effects on TRPV1 or TRPA1 channels. Thus, the tryptamine scaffold appears as an attractive template for the design of highly specific and potent TRPM8 modulators

N-substitued tryptamines as TRPM8 channel modulators

OSTACOLO, CARMINE;Alessia Bertamino;NOVELLINO, ETTORE;
2015-01-01

Abstract

Transient receptor potential melastatin type-8 (TRPM8), is a transmembrane, non selective Ca2+ permeable cation channel. Despite this channel is mainly considered as the major sensor for peripheral innocuous cool, its modulation is responsible for several physiopathological processes. In fact, TRPM8 antagonists have been reported to induce strong analgesia [1], whereas the same effect has been described when agonists are administered in a in a range of very low concentrations [2]. TRPM8 agonists have been also proposed as useful diagnostic and therapeutic tools for the treatment of prostate cancer and benign prostate hyperplasia (BPH) [3], while antagonists have been investigated for the treatment of overactive and painful bladder syndromes [4]. Thus, increasing efforts in the last few years have been dedicated to the design of selective and potent TRPM8 ligands. Starting from these evidence, the aim of the present study has been to synthesize and evaluate the biological activity of a small library of N-substituted tryptamines (Figure 1) as TRPM8 modulators. These derivatives were preliminary screened for their activity and selectivity among TRP channels by in vitro Ca2+-imaging experiments using Fluo4-NW in cells stably expressing TRPM8 (HEK), TRPV1 (SH-SY5Y ) or TRPA1 (IMR90) channels. The most active molecules were further investigated by electrophysiological recordings in HEK cells transiently expressing TRPM8 channels. One rather potent agonist (IGM01-5, EC50= 40±3 μM) and one antagonist (IGM01-18, IC50=367±24 nM) of TRPM8 channels were identified. These derivatives failed to show functional effects on TRPV1 or TRPA1 channels. Thus, the tryptamine scaffold appears as an attractive template for the design of highly specific and potent TRPM8 modulators
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11386/4812106
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact