A PHARMACOLOGICAL PROFILE OF THE NOVEL, PERIPHERALLY-SELECTIVE KAPPA-OPIOID RECEPTOR AGONIST, EMD-61753

1 The pharmacological properties of the novel diarylacetamide kappa-op ioid receptor agonist, EMD 61753, have been compared with those of ICI 197067 (a centrally-acting kappa agonist) and ICI 204448 (a periphera lly-selective kappa agonist). 2 EMD 61753 binds with high affinity (IC 50 5.6 nM) and selectivity (kappa:mu:delta:sigma binding ratio 1:536: 125:> 1,786) to kappa-opioid receptors and is a full and potent (IC50 54.5 nM) agonist in an in vitro assay for kappa-opioid receptors (rabb it vas deferens preparation). 3 Systemically-applied [C-14]-EMD 61753 is found in high concentrations in the lungs, liver, adrenal glands an d kidneys. Considerably less radioactivity is detected in the whole br ain, and this radioactivity is concentrated in the region of the cereb ral ventricles in the choroid plexuses. EMD 61753 penetrates only poor ly into the CNS. 4 EMD 61753 was weakly effective in pharmacological t ests of central activity. This compound reversed haloperidolol-induced DOPA accumulation in the nucleus accumbens of the rat only at a dose of 30 mg kg(-1), s.c., (doses of 0.1, 1.0 and 10 mg kg(-1), s.c., and 1.0, 10 and 100 mg kg(-1), p.o., were inactive). Hexobarbitone-induced sleeping in mice was prolonged by EMD 61753 at threshold doses of 10 mg kg(-1), s.c., and 100 mg kg(-1), p.o., whereas the motor performanc e of rats in the rotarod test was impaired by EMD 61753 with an ID50 v alue of 453 mg kg(-1), s.c. 5 EMD 61753 produced dose-dependent, nalox one-reversible antinociception in the mouse formalin test (1st phase I D50 1.9 mg kg(-1), s.c., and 10.4 mg kg(-1), p.o.; 2nd phase ID50 0.26 mg kg(-1), s.c., and 3.5 mg kg(-1), p.o.) and rodent abdominal constr iction test (IDS, mouse 1.75 mg kg(-1), s.c., and 8.4 mg kg(-1), p.o.; ID50 rat 3.2 mg kg(-1), s.c., and 250 mg kg(-1), p.o.). EMD 61753 was inactive, or only weakly effective, in the rat pressure test under no rmalgesic conditions. After the induction of hyperalgesia with carrage enin, however, this compound elicited potent, dose-dependent (ID50 0.0 8 mg kg(-1), s.c., and 6.9 mg kg(-1), p.o., after remedial application , and 0.2 mg kg(-1), s.c., and 3.1 mg kg(-1), p.o., after prophylactic application) and naloxone-reversible antinociception. The antinocicep tive action of systemically-applied (50 mg kg(-1), p.o.) EMD 61753 in the hyperalgesic pressure test was completely inhibited by injection o f the kappa-opioid antagonist norbinaltorphimine (100 mu g) into the i nflamed tissue, a result which indicates that this opioid effect is me diated peripherally. 6 Cutaneous plasma protein extravasation produced by antidromic electrical stimulation of the rat saphenous nerve was d ose-dependently inhibited by systemically-applied EMD 61753 (ID50 valu es 3.7 mg kg(-1), s.c., and 35.8 mg kg(-1), p.o.), and this effect was completely antagonized by intraplantar application of norbinaltorphim ine (50 mu g). Extravasation elicited by the intraplantar application of substance P (10 mu g) was not influenced by the administration of E MD 61753. 7 EMD 61753 produced dose-dependent diuresis in non-hydrated rats at doses of and above 1.0 mg kg(-1), s.c., and 10 mg kg(-1), p.o ., and in saline-loaded rats at doses of and above 10 mg kg(-1), s.c., and 30 mg kg(-1), p.o. 8 The prostaglandin-mediated fall in mean arte rial blood pressure elicited in anaesthetized rats by i.v. application of arachidonic acid was not inhibited by prior treatment with EMD 617 53 (10 mg kg(-1), p.o.). Thus, a blockade of prostaglandin synthesis v ia inhibition of cyclo-oxygenase activity does not contribute to the i n vivo effects of EMD 61753 and its metabolites. 9 The present experim ents therefore indicate that EMD 61753 is a potent, selective and oral ly-effective full kappa-opioid receptor agonist which has a limited ab ility to penetrate the blood-brain barrier and elicit centrally-mediat ed sedation, putative aversion, diuresis, and antinociception. The inh ibitory actions of systemically-applied EMD 61753 against hyperalgesic pressure nociception and neurogenic inflammation are mediated periphe rally, probably by opioid receptors on the endings of sensory nerve fi bres.