CI-977, A novel, selective and exceptionally potent kappa opioid agonist

Abstract

Microdialysis was utilized to evaluate the effects of selective κ-opioid receptor agonists on dopamine levels in the dorsal caudate of conscious rats. Subcutaneous administration of equivalent antinociceptive doses of spiradoline -(±)-(5α,7α,8β)-3,4- dichloro-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]bennzeneacetamide - (U62066; 12 mg/kg), BRL 52656 - (2S)-1- [(4-triflouromethylphenyl)acetyl]-2-[(1-pyrrolidinyl)methyl]piperidine - (2 mg/kg) and enadoline - (−)-(5β,7β,8α)-N-methyl-N- [7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]benzo[b]furan-4-acetamide - (CI-977; 0.1 mg/kg) produced similar, statistically significant decreases in dorsal caudate dopamine levels; BRL 53001 - (2S)-2-(dimethylaminomethyl)-1-[5,6,7,8-tetrahydro-5-oxo-2- naphthyl)acetyl]piperidine - (12 mg/kg) was, however, without effect. At a higher dose (36 mg/kg), BRL 53001 also caused a significant reduction in dopamine levels. BRL 52974 - 4-(1-pyrrolidinylmethyl)5-[(3,4-dichlorophenyl)acetyl]-4,5,6,7-tetrahydro-imidazo[4,5-c]pyridine , a selective κ-opioid receptor agonist with limited ability to cross the blood brain barrier or produce antinociceptive effects, had no effect on dopamine levels at 10 mg/kg s.c. Overall, these findings suggest that selective κ-opioid receptor agonists decrease dopamine levels in the dorsal caudate of rats via a central locus of action. Furthermore, compared to other κ-opioid receptor agonists, BRL 53001 appears to have a reduced propensity to decrease dopamine levels at equianalgesic doses.