(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

摘要

Spiroxatrine was identified as a moderately potent (Ki=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 (Ki=7.3 nM).NNC 63-0532 showed only moderate affinity for the following receptors (Ki values in parentheses): μ-opioid (140 nM), κ-opioid (405 nM), dopamine D2S (209 nM), dopamine D3 (133 nM) and dopamine D4.4 (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 (EC50=305 nM), a much weaker agonist at the μ-opioid receptor (EC50>10 μM) and an antagonist or weak partial agonist at dopamine D2S (IC50=2830 nM).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.