Development of selective sigma-1 receptor ligands with antiallodynic activity: A focus on piperidine and piperazine scaffolds

• Published in: European journal of medicinal chemistry 2025-01, Vol.281, p.117037, Article 117037
• Main Authors: Cosentino, Giuseppe, Dichiara, Maria, Ambrosio, Francesca Alessandra, Leotta, Claudia Giovanna, Costa, Giosuè, Procopio, Francesca, Costanzo, Giuliana, Raffa, Alessandro, Artacho-Cordón, Antonia, Ruiz-Cantero, M. Carmen, Pasquinucci, Lorella, Marrazzo, Agostino, Pitari, Giovanni Mario, Cobos, Enrique J., Alcaro, Stefano, Amata, Emanuele
• Format: Article
• Language: English
• Subjects: Analgesia; Analgesics - chemical synthesis; Analgesics - chemistry; Analgesics - pharmacology; Animals; Dose-Response Relationship, Drug; Drug Development; Humans; Hyperalgesia - chemically induced; Hyperalgesia - drug therapy; Ligands; Male; Mice; Mice, Knockout; Models, Molecular; Molecular modeling; Molecular Structure; Pain; Piperazine - chemical synthesis; Piperazine - chemistry; Piperazine - pharmacology; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - pharmacology; Receptors, sigma - antagonists & inhibitors; Receptors, sigma - metabolism; Sigma-1 Receptor; Sigma-1 receptor antagonist; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2024.117037

The design and synthesis of a series of piperidine and piperazine-based derivatives as selective sigma receptor (SR) ligands associated with analgesic activity, are the focus of this work. In this study, affinities at S1R and S2R were measured, and molecular modeling studies were performed to investigate the binding pose features. The most promising compounds were subjected to in vitro toxicity testing and subsequently screened for in vivo analgesic properties. Compounds 12a (AD353) and 12c (AD408) exhibited negligible in vitro cellular toxicity and high potency both in a model of capsaicin-induced allodynia and in PGE2-induced mechanical hyperalgesia. Functional activity experiments showed that S1R antagonism is needed for the effects of these compounds, since the effect was reversed by PRE-084 or absent in KO mice. In addition, 12a exhibited a favorable pharmacokinetic profile, confirming its therapeutic value in treating allodynic conditions. Moreover, a computational model was developed in order to help the understanding about the mechanism of action of most active compounds. [Display omitted] •A novel class of piperidine and piperazine-based derivatives as selective SR ligands were designed and synthesized.•The affinity, biological potency and efficacy of these compounds were assessed through both in vitro and in vivo experiments.•Compound 12a (AD353) had excellent in vivo antiallodynic potency, along with a favorable safety and pharmacokinetic profile.•In silico models gave an explanation about the molecular recognition of most active compounds within the SR binding cleft.