Evaluation of the antinociceptive and anti-inflammatory activity of 2-morpholinoethyl 2-(naphthalen-2-yloxy)acetate and 2-(piperidin-1-yl)ethyl 2-(naphthalen-2-yloxy)acetate as novel Sigma-1 receptor antagonists

The sigma-1 receptor represents a highly promising therapeutic alternative to classical opioids and NSAIDs for the management of pain and inflammation. The development of highly selective compounds with optimal pharmacokinetic profiles remains a critical challenge in medicinal chemistry. In this study, novel ligands were designed through a pharmacophoric hybridization strategy based on the Glennon model, coupling the naphthalene nucleus of S1RA with haloperidol-derived cyclic amines via an ester linker. Following computational validation through molecular docking at the sigma-1 receptor, two main molecules were chemically synthesized: Piperiéster (piperidine derivative) and Morfoéster (morpholine derivative). Their biological efficacy was subsequently evaluated in vivo using murine models of pain (hot plate and formalin tests) and inflammation (croton oil-induced auricular edema and carrageenan-induced plantar edema). It was observed that both molecules showed a clear dose-dependent antinociceptive effect in the hot plate test, reaching 80-90% efficacy, indicating their ability to cross the blood-brain barrier. In the formalin model, Morfoéster proved superior for inflammatory pain, achieving nearly 70% inhibition in Phase II, characteristic of central sensitization blockade. Conversely, in systemic inflammation evaluations (plantar edema), Piperiéster exhibited a remarkable 81% inhibition. Both compounds also successfully reduced topical inflammation by more than 70% in the auricular edema model. These results allow us to conclude that the hybridization strategy successfully yielded novel sigma-1 receptor ligands with proven biological activity. Morfoéster emerges as an optimal clinical tool for central and inflammatory pain, while Piperiéster demonstrates a notable capacity to curb systemic inflammation. Both derivatives represent excellent starting points for the development of safer new therapies without the side effects of conventional treatments.