(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

Spiroxatrine was identified as a moderately potent ( K i =118 n M ) 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 n M ). NNC 63‐0532 showed only moderate affinity for the following receptors ( K i values in parentheses): μ‐opioid (140 n M ), κ‐opioid (405 n M ), dopamine D 2S (209 n M ), dopamine D 3 (133 n M ) and dopamine D 4.4 (107 n M ) 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 n M ), a much weaker agonist at the μ‐opioid receptor (EC 50 >10 μ M ) and an antagonist or weak partial agonist at dopamine D 2S (IC 50 =2830 n M ). Thus, NNC 63‐0532 is a novel non‐peptide agonist with ∼12 fold selectivity for ORL1 and may be useful for exploring the physiological roles of this receptor owing to its brain‐penetrating properties.British Journal of Pharmacology (2000) 131 , 903–908; doi: 10.1038/sj.bjp.0703661