Designing bifunctional NOP receptor-mu opioid receptor ligands from NOP-receptor selective scaffolds. Part II

Bioorg Med Chem. 2014 Apr 15;22(8):2508-16. doi: 10.1016/j.bmc.2014.02.047.

V Blair Journigan ¹, Willma E Polgar ², Taline V Khroyan ², Nurulain T Zaveri ³

Affiliations

1 Astraea Therapeutics, LLC., 320 Logue Avenue, Mountain View, CA 94043, United States.
2 SRI International, Biosciences Division, 333 Ravenswood Avenue, Menlo Park, CA 94025, United States.
3 Astraea Therapeutics, LLC., 320 Logue Avenue, Mountain View, CA 94043, United States. Electronic address: nurulain@astraeatherapeutics.com.

PMID: 24657054 DOI: 10.1016/j.bmc.2014.02.047

Abstract

The nociceptin Opioid Receptor (NOP) and its endogenous peptide ligand nociceptin/orphanin FQ have been shown to modulate the pharmacological effects of the classical Opioid Receptor system. Suppression of opioid-induced reward associated with mu-opioid receptor (MOP)-mediated analgesia, without decreasing anti-nociceptive efficacy, can potentially be achieved with NOP agonists having bifunctional agonist activity at MOP, to afford 'non-addicting' analgesics. In Part II of this series, we describe a continuing structure-activity relationship (SAR) study of the NOP-selective piperidin-4-yl-1,3-dihydroindol-2-one scaffold, to obtain bifunctional activity at MOP, and a suitable ratio of NOP/MOP agonist activity that produces a non-addicting analgesic profile. The SAR reported here is focused on the influence of various piperidine nitrogen aromatic substituents on the ratio of binding affinity and intrinsic activity at both the NOP and MOP receptors.

Keywords

Bifunctional ligands; N/OFQ; NOP/opioid; Nociceptin receptor; Nociceptin/orphanin FQ.

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