title: (8-Naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza-spiro[4. 5]dec-3-yl)-acetic acid methyl ester (NNC 63-0532) is a novel potent nociceptin receptor agonist.
abstract: Spiroxatrine was identified as a moderately potent (K:(i)=118 nM) but non-selective agonist at the human nociceptin/orphanin FQ receptor, ORL1. This compound was subject to chemical modification and one of the resulting compounds, (8-naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza-s piro[4. 5]dec-3-yl)-acetic acid methyl ester (NNC 63-0532) was shown to have high affinity for ORL1 (K:(i)=7.3 nM). NNC 63-0532 showed only moderate affinity for the following receptors (K:(i) values in parentheses): mu-opioid (140 nM), kappa-opioid (405 nM), dopamine D(2S) (209 nM), dopamine D(3) (133 nM) and dopamine D(4.4) (107 nM) out of 75 different receptors, ion-channels and transporters. In functional assays, NNC 63-0532 was shown to be an agonist at ORL1 (EC(50)=305 nM), a much weaker agonist at the mu-opioid receptor (EC(50)>10 microM) and an antagonist or weak partial agonist at dopamine D(2S) (IC(50)=2830 nM). Thus, NNC 63-0532 is a novel non-peptide agonist with approximately 12 fold selectivity for ORL1 and may be useful for exploring the physiological roles of this receptor owing to its brain-penetrating properties.
authors.affiliation: Novo Nordisk A/S, Department of Molecular Pharmacology, Novo Nordisk Park, Denmark.
authors.forename: C
authors.initials: C
authors.lastname: Thomsen
authors.forename: R
authors.initials: R
authors.lastname: Hohlweg
mesh_terms: D000085:Acetates / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D006224:Cricetinae; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D051381:Rats; D011957:Receptors, Opioid / Q000819:agonists* / Q000378:metabolism; D013141:Spiro Compounds / Q000378:metabolism / Q000494:pharmacology*; D000094942:Nociceptin Receptor
chemical_list: C417686:(8-naphthalen-1-ylmethyl-4-oxo-1-phenyl-1,3,8-triaza-spiro(4.5)-dec-3-yl)acetic acid methyl ester; D000085:Acetates; D011957:Receptors, Opioid; D013141:Spiro Compounds; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000094942:Nociceptin Receptor