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

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  • Theme: Celebrating Women in the Pharmaceutical Sciences
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Abstract

The nociceptin opioid receptor (NOP), the fourth member of the opioid receptor family, and its endogenous peptide ligand, nociceptin or orphanin FQ (N/OFQ), play a vital role in several central nervous system pathways regulating pain, reward, feeding, anxiety, motor control and learning/memory. Both selective NOP agonists as well as bifunctional agonists at the NOP and mu opioid receptor (MOP) have potential therapeutic applications in CNS disorders related to these processes. Using Surflex-Dock protocols, we conducted a computational structure-activity study of four scaffold classes of NOP ligands with varying NOP-MOP selectivity. By docking these compounds into the orthosteric binding sites within an active-state NOP homology model, and an active-state MOP crystal structure, the goal of this study was to use a structure-based drug design approach to modulate NOP affinity and NOP vs. MOP selectivity. We first docked four parent compounds (no side chain) to determine their binding interactions within the NOP and MOP binding pockets. Various polar sidechains were added to the heterocyclic A-pharmacophore to modulate NOP ligand affinity. The substitutions mainly contained a 1-2 carbon chain with a polar substituent such as an amine, alcohol, sulfamide, or guanidine. The SAR analysis is focused on the impact of structural changes in the sidechain, such as chain length, hydrogen bonding capability, and basic vs neutral functional groups on binding affinity and selectivity at both NOP and MOP receptors. This study highlights structural modifications that can be leveraged to rationally design both selective NOP and bifunctional NOP-MOP agonists with different ratios of functional efficacy.

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Acknowledgements

This work was supported by grants R01DA027811 (N.T.Z.), R43NS070664 (N.T.Z.), R44DA042465 (N.T.Z) and NIAAA Contracts HHSN275201300005C and HHSN275201500005C from the National Institutes of Health.

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Authors and Affiliations

  1. Astraea Therapeutics, LLC, 320 Logue Avenue, Mountain View, California, 94043, USA

    Michael E. Meyer, Arpit Doshi, Dennis Yasuda & Nurulain T. Zaveri

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  1. Michael E. Meyer
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  2. Arpit Doshi
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  4. Nurulain T. Zaveri
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Contributions

M.E.M and A.D. contributed equally to this work. M.E.M, A.D., and D.Y. conducted the design, chemical synthesis, and SAR analysis of the NOP ligands. A.D. conducted the molecular docking experiments. N.T.Z conducted the design and the SAR and data analysis, and supervised the study.

Corresponding author

Correspondence to Nurulain T. Zaveri.

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Meyer, M.E., Doshi, A., Yasuda, D. et al. Structure-Based SAR in the Design of Selective or Bifunctional Nociceptin (NOP) Receptor Agonists. AAPS J 23, 68 (2021). https://doi.org/10.1208/s12248-021-00589-7

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