Novel hexahydrospiro[piperidine-4,1'-pyrrolo[3,4-c]pyrroles]: highly selective small-molecule nociceptin/orphanin FQ receptor agonists.
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.
Kolczewski
Sabine
S
Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd., Grenzacher Strasse 124, CH-4070 Basel, Switzerland. sabine.kolczewski@roche.com
Adam
Geo
G
Cesura
Andrea M
AM
Jenck
François
F
Hennig
Michael
M
Oberhauser
Thomas
T
Poli
Sonia M
SM
Rössler
Felix
F
Röver
Stephan
S
Wichmann
Jürgen
J
Dautzenberg
Frank M
FM
D001667:Binding, Competitive; D002460:Cell Line; D018360:Crystallography, X-Ray; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D011957:Receptors, Opioid / Q000819:agonists*; D017465:Receptors, Opioid, delta / Q000819:agonists; D017473:Receptors, Opioid, kappa / Q000819:agonists; D017450:Receptors, Opioid, mu / Q000819:agonists; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor
C470756:1-(4-isopropylcyclohexyl)-5'-methyl-2'-phenylhexahydrospiro(piperidine-4,1'-pyrrolo(3,4-c)pyrrole); D011725:Pyridines; D011758:Pyrroles; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013141:Spiro Compounds; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000242:Cyclic AMP; D000094942:Nociceptin Receptor; C000722283:OPRL1 protein, human