(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

1 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-spiro[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). 2 NNC 63-0532 showed only moderate affinity for the following receptors (Ki 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. 3 In functional assays, NNC 63-0532 was shown to be an agonist at ORL1 (EC50 = 305 nM), a much weaker agonist at the mu -opioid receptor (EC50 = >10 muM) and an antagonist or weak partial agonist at dopamine D-2S (IC50 = 2830 nM). 4 Thus, NNC 63-0532 is a novel non-peptide agonist with similar to 12 fold selectivity for ORL1 and may be useful for exploring the physiological roles of this receptor owing to its brain-penetrating properties.