| Summary: | 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<sup>2,5</sup>]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<sup>3,8</sup>]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.
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