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

• Main Authors: Sandra Piras, Gabriele Murineddu, Giovanni Loriga, Antonio Carta, Enrica Battistello, Stefania Merighi, Stefania Gessi, Paola Corona, Battistina Asproni, Roberta Ibba, Veronika Temml, Daniela Schuster, Gérard Aimè Pinna
• Format: Article
• Language: English
• Published: MDPI AG 2021-09-01
• Series: Molecules
• Subjects: μ-receptors affinity; analgesic activity; 9,10-diazatricyclo[4.2.1.1^2,5]decane (DTD); 2,7-diazatricyclo[4.4.0.0^3,8]decane; DTD derivatives; rigid benzo-condensed structure
• Online Access: https://www.mdpi.com/1420-3049/26/18/5448

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[4.2.1.1^2,5]decane (compounds <b>20</b>–<b>23</b>, <b>53</b>, <b>57</b> and <b>59</b>) and 2-propionyl-7-substituted-2,7-diazatricyclo[4.4.0.0^3,8]decane (compounds <b>24</b>–<b>27</b>, <b>54</b>, <b>58</b> and <b>60</b>) 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 <b>20</b>, <b>21</b>, <b>24</b>, <b>26</b> and <b>53</b>, 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.