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Chambers, Dana R; Sulima, Agnieszka; Luo, Dan; Prisinzano, Thomas E; Goldberg, Alexander; Xie, Bing; Shi, Lei; Paronis, Carol A; Bergman, Jack; Nassehi, Nima; Selley, Dana E; Imler, Gregory H; Jacobson, Arthur E; Rice, Kenner C
Molecules (Basel, Switzerland), 09/2022, Volume: 27, Issue: 19Journal Article
Four sets of diastereomeric C9-alkenyl 5-phenylmorphans, varying in the length of the C9-alkenyl chain, were designed to examine the effect of these spatially distinct ligands on opioid receptors. Functional activity was obtained by forskolin-induced cAMP accumulation assays and several compounds were examined in the 35SGTPgS assay and in an assay for respiratory depression. In each of the four sets, similarities and differences were observed dependent on the length of their C9-alkenyl chain and, most importantly, their stereochemistry. Three MOR antagonists were found to be as or more potent than naltrexone and, unlike naltrexone, none had MOR, KOR, or DOR agonist activity. Several potent MOR full agonists were obtained, and, of particular interest partial agonists were found that exhibited less respiratory depression than that caused by morphine. The effect of stereochemistry and the length of the C9-alkenyl chain was also explored using molecular modeling. The MOR antagonists were found to interact with the inactive (4DKL) MOR crystal structures and agonists were found to interact with the active (6DDF) MOR crystal structures. The comparison of their binding modes at the mouse MOR was used to gain insight into the structural basis for their stereochemically induced pharmacological differences.
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