A pharmacological profile of the novel, peripherally‐selective k‐opioid receptor agonist, EMD 61753

Abstract

1 The pharmacological properties of the novel diarylacetamide .c-opioid receptor agonist, EMD 61753, have been compared with those of ICI 197067 (a centrally-acting K agonist) and ICI 204448 (a peripherally-selective Kc agonist).2 EMD 61753 binds with high affinity (IC50 5.6 nM) and selectivity (K:ft:6:a binding ratio 1:536:125:> 1,786) to ic-opioid receptors and is a full and potent (IC50 54.5 nM) agonist in an in vitro assay for K-opioid receptors (rabbit vas deferens preparation). 3 Systemically-applied ['4C]-EMD 61753 is found in high concentrations in the lungs, liver, adrenal glands and kidneys. Considerably less radioactivity is detected in the whole brain, and this radioactivity is concentrated in the region of the cerebral ventricles in the choroid plexuses. EMD 61753 penetrates only poorly into the CNS. 4 EMD 61753 was weakly effective in pharmacological tests of central activity. This compound reversed haloperidolol-induced DOPA accumulation in the nucleus accumbens of the rat only at a dose of 30mgkg-', s.c., (doses of 0.1, 1.0 and 10mgkg-', s.c., and 1.0, 10 and 100mgkg-', p.o., were inactive). Hexobarbitone-induced sleeping in mice was prolonged by EMD 61753 at threshold doses of 10 mg kg-', s.c., and 100 mg kg-', p.o., whereas the motor performance of rats in the rotarod test was impaired by EMD 61753 with an IDm, value of 453 mg kg-', s.c.5 EMD 61753 produced dose-dependent, naloxone-reversible antinociception in the mouse formalin test (1st phase ID50 1.9 mg kg-', s.c., and 10.4mg kg-', p.o.; 2nd phase IDm 0.26mg kg', s.c., and 3.5 mg kg-', p.o.) and rodent abdominal constriction test (ID50 mouse 1.75 mg kg-', s.c., and 8.4mg kg-', p.o.; IDs rat 3.2mg kg', s.c., and 250mg kg', p.o.). EMD 61753 was inactive, or only weakly effective, in the rat pressure test under normalgesic conditions. After the induction of hyperalgesia with carrageenin, however, this compound elicited potent, dose-dependent (IDs 0.08 mg kg-', s.c., and 6.9 mg kg-', p.o., after remedial application, and 0.2 mg kg-', s.c., and 3.1 mg kg-', p.o., after prophylactic application) and naloxone-reversible antinociception. The antinociceptive action of systemically-applied (50 mg kg-', p.o.) EMD 61753 in the hyperalgesic pressure test was completely inhibited by injection of the K-opioid antagonist norbinaltorphimine (100 Lg) into the inflamed tissue, a result which indicates that this opioid effect is mediated peripherally. 6 Cutaneous plasma protein extravasation produced by antidromic electrical stimulation of the rat saphenous nerve was dose-dependently inhibited by systemically-applied EMD 61753 (ID13 values 3.7 mg kg', s.c., and 35.8 mg kg', p.o.), and this effect was completely antagonized by intraplantar application of norbinaltorphimine (50 pg). Extravasation elicited by the intraplantar application of substance P (10 pg) was not influenced by the administration of EMD 61753.7 EMD 61753 produced dose-dependent diuresis in non-hydrated rats at doses of and above 1.0 mg kg-', s.c., and 10 mg kg-', p.o., and in saline-loaded ra...

Dynorphin A, kappa opioid receptors and the antinociceptive efficacy of asimadoline in streptozotocin-induced diabetic rats

“…Conversely, the highest dose used (15 mg/kg) was effective against tactile allodynia, but efficacy against phase 2 of the formalin test was lost. A similar loss of efficacy of asimadoline in high doses has been previously reported in studies of paw pressure sensitivity in normal rats [16]. The different dose:effect curves of asimadoline against tactile allodynia and formalin-evoked hyperalgesia in diabetic rats could reflect different causes of the two disorders, as suggested by their differential sensitivity to aldose reductase inhibitors [22], and/or distinct sites of action of asimadoline.…”

“…In addition to opioid-associated antinociceptive properties, there is strong evidence that dynorphin also contributes to allodynia and hyperalgesia after nerve injury and helps sustain persistent neuropathic pain [11][12][13][14][15][16][17][18][19][20][21][22][23]. Intrathecal injection of dynorphin A induces prolonged tactile allody- nia that is blocked by antagonists of NMDA, but not opioid receptors [7].…”

“…Indeed, and in contrast to tactile allodynia, intraplantar injection of the KOR antagonist nor-BNI did not block the action of asimadoline on formalin-evoked hyperalgesia. However, spinal delivery of nor-BNI was effective, suggesting that even limited penetration of asimadoline in the central nervous system [16,41] could play a role in its capacity to ameliorate formalin-evoked hyperalgesia.…”

“…Our findings prompted us to subsequently explore the ability of asimadoline (EMD61753), a KOR agonist with restricted ability to cross the blood-brain-barrier [16], to alleviate tactile allodynia and formalin-evoked hyperalgesia in diabetic rats. Asimadoline has antinociceptive properties in a number of inflammatory pain models [16][17][18][19] and alleviated mechanical hyperalgesia after sciatic nerve ligation [20], but its potential efficacy against diabetes-induced neuropathic pain has not yet been reported.…”

Blood-Brain Barrier Permeation: Molecular Parameters Governing Passive Diffusion

“…No side effects were observed, even at high concentrations (Seppala & Savolainen, 1982) which suggests that it does not reach the brain (Reece et al, 1994). Asimadoline reaches the brain only to a limited extent as shown by means of in vitro experiments (Barber et al, 1994). Domperidone is a peripherally active dopamine antagonist.…”