Biological Effects on μ-Receptors Affinity and Selectivity of Arylpropenyl Chain Structural Modification on Diazatricyclodecane Derivatives

• Published in: Molecules (Basel, Switzerland) Vol. 26; no. 18; p. 5448
• Main Authors: Piras, Sandra, Murineddu, Gabriele, Loriga, Giovanni, Carta, Antonio, Battistello, Enrica, Merighi, Stefania, Gessi, Stefania, Corona, Paola, Asproni, Battistina, Ibba, Roberta, Temml, Veronika, Schuster, Daniela, Pinna, Gérard Aimè
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 07.09.2021; MDPI
• Subjects: 2,7-diazatricyclo[4.4.0.03,8]decane; 9,10-diazatricyclo[4.2.1.12,5]decane (DTD); Affinity; Agonists; analgesic activity; Analgesics; Biological effects; Chromatography; Chronic pain; DTD derivatives; Ligands; Models, Molecular; Narcotics; Nervous system; Opioid receptors; Pain; Peptides; Receptors, Opioid; rigid benzo-condensed structure; Selectivity; Spinal cord; Substitutes; μ-receptors affinity; rigid benzo-condensed structure; 9,10-diazatricyclo[4.2.1.12,5]decane (DTD); analgesic activity; 2,7-diazatricyclo[4.4.0.03,8]decane; DTD derivatives; μ-receptors affinity
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules26185448

Opioid analgesics are clinically used to relieve severe pain in acute postoperative and cancer pain, and also in the long term in chronic pain. The analgesic action is mediated by μ-, δ-, and κ-receptors, but currently, with few exceptions for k-agonists, μ-agonists are the only ones used in therapy. Previously synthesized compounds with diazotricyclodecane cores (DTDs) have shown their effectiveness in binding opioid receptors. Fourteen novel diazatricyclodecanes belonging to the 9-propionyl-10-substituted-9,10-diazatricyclo[4.2.1.1 ]decane (compounds - , , and ) and 2-propionyl-7-substituted-2,7-diazatricyclo[4.4.0.0 ]decane (compounds - , , and ) series, respectively, have been synthesized and their ability to bind to the opioid μ-, δ- and κ-receptors was evaluated. Five of these derivatives, compounds , , , and , showed μ-affinity in the nanomolar range with a negligible affinity towards δ- and κ-receptors and high μ-receptor selectivity. The synthesized compounds showed μ-receptor selectivity higher than those of previously reported methylarylcinnamyl analogs.