targeting the transient receptor potential vanilloid type 1 channel: design and pharmacological characterization of new 4-(thiophen-2-yl)butanoic acid amides as trpv1 ligands

The vanilloid receptor TRPV1, responsible for binding the natural pungent principle of capsicum, capsaicin, is considered as a highly validated pain target being abundantly expressed in sensory neurons [1] but also in higher brain structures involved in pain processing [2]. Both agonists and antagonists of this non-selective cation channel are being evaluated as potential analgesics; in fact, its agonists lead to receptor desensitization, silencing previously excited neurons, while its antagonists relieve pain behaviors in animal models of inflammation and cancer. Some endogenous arachidonic acid amides are activators of TRPV1, mainly two endocannabinoids anandamide (AEA) and arachidonoyldopamine (NADA), and compound AM404, the N-acyl derivative of 4-aminophenol with arachidonic acid [3]. An ultrapotent capsaicin natural analogue is resiniferatoxin (RTX), while the first generation of TRPV1 antagonists is capsazepine [4]. Inside this very extensive chemical diversity, the common determinants seem to be a polar head and a lipophylic backbone linked by an amide group. The aim of this study is to design and synthesize new TRPV1 ligands characterized by a 4-(thiophen-2-yl)butanoic acid amide moiety endowed potential agonist or antagonist activity and investigate how the chemical decoration of the thiophene-ring and/or the electronic/steric properties of amide can affect the interaction with the vannilloid receptor.