Novel Hexahydrospiro[piperidine-4,1‘-pyrrolo[3,4-c]pyrroles]:  Highly Selective Small-Molecule Nociceptin/Orphanin FQ Receptor Agonists

Abstract

Novel hexahydrospiro[piperidine-4,1'-pyrrolo[3,4-c]pyrroles that act as potent and selective orphanin FQ/nociceptin (N/OFQ) receptor (NOP) agonists were identified. The best compound, (+)-5a, potently inhibited 3H-N/OFQ binding to the NOP receptor (K(i) = 0.49 nM) but was >1000-fold less potent in binding to MOP, KOP, and DOP opiate receptors. Further, (+)-5a potently stimulated GTP gamma S binding to NOP membranes (EC50 = 65 nM) and inhibited forskolin-mediated cAMP accumulation in NOP-expressing cells (EC50 = 9.1 nM) with a potency comparable to that of the natural peptide agonist N/OFQ. These results indicate that (+)-5a is a highly selective and potent small-molecule full agonist of the NOP receptor.

Quantitative study of [Tyr10]nociceptin/orphanin FQ (1-11) at NOP receptors in rat periaqueductal gray and expressed NOP receptors in HEK293 cells

“…(+)-5a Compound was 380-1600 times less potent than N/OFQ. In the study of Kolczewski et al (2003), (+)-5a Compound was 25 folds less potent than N/ OFQ in reducing cAMP accumulation in human NOP receptors expressed in HEK293 cells. The efficacy of [Tyr 10 ]N/OFQ(1-11) was comparable to that of N/OFQ at either NOP cells or NOP-MOP cells (Fig.…”

Relaxin Receptors - New Drug Targets for Multiple Disease States

“…For a very comprehensive overview on recent advances in the development of new N/OFQ ligands, see also the Expert Opinion by Bignan et al [20]. [39,40] (+)-5a compound 0.55 † /65 ‡ 537 † (MOP)* 309 † (KOP) 2138 † (DOP) [41] W-212393 0.5 † 76 † (MOP)* >1000 † (KOP) >1000 † (DOP) 11 † (SERT) [42] 3-(4-piperidinyl)indoles a 18 † /27200 ‡ 500 † (MOP) 1890 † (KOP) >5000 † (DOP) [43] 3-(4-piperidinyl)pyrrolo [ (+)-5a compound: (3aS,6aR)-1-(cis-4-Isopropylcyclohexyl)-5'-methyl-2'-phenylhexahydrospiro[piperidine-4,1'-pyrrolo [3,4-c]pyrrole]. W-212393: 2-{3-[1-((1R)-acenaphthen-1-yl)piperidin-4-yl]-2,3-dihydro-2-oxo-benzimidazol-1-yl}-N-methylacetamide.…”

“…In 2003, F. Hoffmann-La Roche Ltd. presented another selective non-peptide agonist, (+)-5a compound [41] (Table 1), which acted as a full agonist, with subnanomolar affinity, at cloned NOP receptors in two different in vitro assays and showed selectivity over 30 different receptors and channels. Only at concentrations of 10 μM or above, did this compound interact with histamine H 3 , muscarinic and receptors as well as Na + channels [41].…”

“…Only at concentrations of 10 μM or above, did this compound interact with histamine H 3 , muscarinic and receptors as well as Na + channels [41]. Interestingly, we found this compound displayed similar pharmacological characteristics as Ro 64-6198 in the NOP receptors of midbrain vlPAG neurons (Liao, Prinssen, Kolczewski and Chiou, unpublished data).…”

The design and synthesis of a novel quinolizidine template for potent opioid and opioid receptor-like (ORL1, NOP) receptor ligands

“…1) was identified as a potent NOP agonist (K i =0.49 nM) with >1000-fold selectivity over the μ, δ, and κ opioid receptors. 25 It is interesting to note that all small-molecule NOP ligands disclosed thus far contain a common piperidine core and bear close structural resemblance to lofentanil and the anilidopiperidine class of opioid ligands. 26 Most of these reported ligands were discovered through high throughput screening of large libraries and the resulting hits were optimized for potency and selectivity versus other opioid receptors by modifying the various substituent groups on the central piperidine ring.…”