Novel hexahydrospiro[piperidine-4,1'-pyrrolo[3,4-c]pyrroles]: highly selective small-molecule nociceptin/orphanin FQ receptor agonists

J Med Chem. 2003 Jan 16;46(2):255-64. doi: 10.1021/jm0209174.

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.

MeSH terms

  • Binding, Competitive
  • Cell Line
  • Crystallography, X-Ray
  • Cyclic AMP / antagonists & inhibitors
  • Cyclic AMP / biosynthesis
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • Humans
  • Nociceptin Receptor
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Pyrroles / chemical synthesis*
  • Pyrroles / chemistry
  • Pyrroles / pharmacology
  • Radioligand Assay
  • Receptors, Opioid / agonists*
  • Receptors, Opioid, delta / agonists
  • Receptors, Opioid, kappa / agonists
  • Receptors, Opioid, mu / agonists
  • Spiro Compounds / chemical synthesis*
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • 1-(4-isopropylcyclohexyl)-5'-methyl-2'-phenylhexahydrospiro(piperidine-4,1'-pyrrolo(3,4-c)pyrrole)
  • Pyridines
  • Pyrroles
  • Receptors, Opioid
  • Receptors, Opioid, delta
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • Spiro Compounds
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Cyclic AMP
  • Nociceptin Receptor
  • OPRL1 protein, human