Structure-Based SAR in the Design of Selective or Bifunctional Nociceptin (NOP) Receptor Agonists

Meyer, Michelle M.; Doshi, Arpit; Yasuda, Dennis; Zaveri, Nurulain T.

doi:10.1208/s12248-021-00589-7

Cited by 2 publications

(2 citation statements)

References 47 publications

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“…The compounds used in this study, AT-034, AT-121, AT-201, and AT-324 are bifunctional NOP-MOP ligands belonging to different chemical scaffolds 41 (Fig. 1 ), designed using medicinal chemistry strategies to have varying levels of NOP and MOP binding affinities and intrinsic efficacies 13 , 35 , 42 , 43 .…”

Section: Discussionmentioning

confidence: 99%

“…AT-324 belongs to yet a different chemical scaffold, the triazaspirodecanone scaffold, which has yielded highly selective NOP ligands such as the selective NOP receptor agonist too compound Ro64-6198 4 . While AT-324 has similarly high binding affinity at NOP as Ro64-6198, medicinal chemistry-driven structural modifications of this scaffold afforded high MOP binding affinity and a bifunctional MOP/NOP agonist efficacy profile in vitro 41 , shown in Tables 1 and 2 . AT-324 also shows potent antinociceptive activity in nonhuman primates (unpublished results).…”

Section: Discussionmentioning

confidence: 99%

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Attenuated G protein signaling and minimal receptor phosphorylation as a biochemical signature of low side-effect opioid analgesics

Dasgupta

Mann

Polgar

et al. 2022

Sci Rep

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Multi-receptor targeting has been proposed as a promising strategy for the development of opioid analgesics with fewer side effects. Cebranopadol and AT-121 are prototypical bifunctional ligands targeting the nociceptin/orphanin FQ peptide receptor (NOP) and µ-opioid receptor (MOP) that elicit potent analgesia in humans and nonhuman primates, respectively. Cebranopadol was reported to produce typical MOP-related side effects such as respiratory depression and reward, whereas AT-121 appeared to be devoid of these liabilities. However, the molecular basis underlying different side effect profiles in opioid analgesics remains unknown. Here, we examine agonist-induced receptor phosphorylation and G protein signaling profiles of a series of chemically diverse mixed MOP/NOP agonists, including cebranopadol and AT-121. We found that these compounds produce strikingly different MOP phosphorylation profiles. Cebranopadol, AT-034 and AT-324 stimulated extensive MOP phosphorylation, whereas AT-201 induced selective phosphorylation at S375 only. AT-121, on the other hand, did not promote any detectable MOP phosphorylation. Conversely, none of these compounds was able to elicit strong NOP phosphorylation and low NOP receptor phosphorylation correlated with partial agonism in a GIRK-channel assay. Our results suggest a close correlation between MOP receptor phosphorylation and side effect profile. Thus, bifunctional MOP/NOP opioid ligands combining low efficacy G protein signaling at both NOP and MOP with no detectable receptor phosphorylation appear to be devoid of side-effects such as respiratory depression, abuse liability or tolerance development, as with AT-121.

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