Asimadoline (EMD-61753)

A pharmacological profile of the novel, peripherally-selective kappa-opioid receptor agonist, EMD 61753

1. The pharmacological properties of the novel diarylacetamide kappa-opioid receptor agonist, EMD 61753, have been compared with those of ICI 197067 (a centrally-acting kappa agonist) and ICI 204448 (a peripherally-selective kappa agonist). 2. EMD 61753 binds with high affinity (IC50 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 (rabbit vas deferens preparation). 3. Systemically-applied [14C]-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 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 performance of rats in the rotarod test was impaired by EMD 61753 with an ID50 value of 453 mg kg-1, s.c. 5. EMD 61753 produced dose-dependent, naloxone-reversible antinociception in the mouse formalin test (1st phase ID50 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 constriction test (ID50 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 normalgesic conditions. After the induction of hyperalgesia with carrageenin, however, this compound elicited potent, dose-dependent (ID50 0.08 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 antinociceptive action of systemically-applied (50 mg kg-1, 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-1, s.c., and 35.8 mg kg-1, p.o.), and this effect was completely antagonized by intraplantar application of norbinaltorphimine (50 microg). Extravasation elicited by the intraplantar application of substance P (10 microg) 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-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 30mgkg-1, p.o.8. The prostaglandin-mediated fall in mean arterial blood pressure elicited in anaesthetized rats by i.v.application of arachidonic acid was not inhibited by prior treatment with EMD 61753 (10mg kg-1,p.o.). Thus, a blockade of prostaglandin synthesis via inhibition of cyclo-oxygenase activity does not contribute to the in vivo effects of EMD 61753 and its metabolites.9 The present experiments therefore indicate that EMD 61753 is a potent, selective and orally-effective full ic-opioid receptor agonist which has a limited ability to penetrate the blood-brain barrier and elicit centrally-mediated sedation, putative aversion, diuresis, and antinociception. The inhibitory actions of systemically-applied EMD 61753 against hyperalgesic pressure nociception and neurogenic inflammation are mediated peripherally, probably by opioid receptors on the endings of sensory nerve fibres.

Peripheral effects of the kappa-opioid agonist EMD 61753 on pain and inflammation in rats and humans

The objective of the present study was to evaluate the effects of EMD 61753 (asimadoline), a kappa-opioid receptor agonist with restricted access to the central nervous system, on postoperative pain in patients who underwent knee surgery and on nociceptive thresholds and inflammation in rats treated with Freund's complete adjuvant. Patients treated with EMD 61753 (10 mg p.o.) tended to report an increase in pain, as evaluated by a visual analog scale and by the time to the first request for and the total amount of supplemental analgesic medication. The global tolerability of EMD 61753 was assessed as significantly inferior to that of a placebo by the investigator. In rats, the bilateral intraplantar (i.pl.) injection of EMD 61753 (0.1-3.2 mg) resulted in dose-dependent antinociception in both inflamed and noninflamed paws, with a peak at 5 min after injection, as evaluated by the paw pressure method. However, at later time points (1 h-4 days), a significant decrease in the paw pressure threshold was observed, confirming its tendency toward a hyperalgesic action in humans. This was accompanied by an increase in paw volume and paw temperature, with a peak at 6 h after injection. EMD 61753 (1.6 mg)-induced analgesia was blocked by the peripheral opioid receptor antagonist naloxone methiodide (2.5-10 mg/kg s.c.) and by the kappa receptor antagonist nor-binaltorphimine (0.1 mg; i.pl.). In contrast, EMD 61753 (1.6 mg)-induced hyperalgesia and increases in paw volume and paw temperature were blocked neither by naloxone methiodide (10-40 mg/kg s.c.) nor by dizocilpine maleate (0.003-0.009 mg i.pl.), a N-methyl-D-aspartic acid receptor antagonist. These data show differentially mediated peripheral actions of EMD 61753: kappa-opioid receptor-induced analgesia and nonopioid, non-N-methyl-D-aspartic acid hyperalgesic and proinflammatory effects.

Asimadoline in the treatment of irritable bowel syndrome

Importance of the field: Irritable bowel syndrome (IBS) represents one of the most common gastrointestinal disorders, with the diarrhea-predominant form (D-IBS) representing an area of high unmet medical need. One difficulty in identifying suitable treatments for IBS is that although there are animal models for the components of IBS, it is not clear whether animals are afflicted by the disease. In a recently completed Phase II study, the kappa-opioid agonist, asimadoline, was shown to be efficacious in a prospectively defined subgroup of D-IBS patients. This study confirmed a good safety profile for asimadoline.
Areas covered in this review: The chemistry, pharmacology, pharmacokinetics, pharmacodynamics and clinical safety and efficacy of asimadoline in relationship to IBS is reviewed. Papers were searched over the past 20 years using the PubMed database and key words 'asimadoline', 'kappa-opioid agonist' and 'irritable bowel syndrome'. Abstracts were reviewed and appropriate full papers were then evaluated.
What the reader will gain: The reader will gain an appreciation of kappa-opioid agonists as IBS treatments.
Take home message: In a prospectively defined, clinically relevant patient subgroup, asimadoline shows efficacy in the treatment of D-IBS.

Novel pharmacology: asimadoline, a kappa-opioid agonist, and visceral sensation

Asimadoline is a potent kappa-opioid receptor agonist with a diaryl acetamide structure. It has high affinity for the kappa receptor, with IC(50) of 5.6 nmol L(-1) (guinea pig) and 1.2 nmol L(-1) (human recombinant), and high selectively with kappa : micro : delta binding ratios of 1 : 501 : 498 in human recombinant receptors. It acts as a complete agonist in in vitro assay. Asimadoline reduced sensation in response to colonic distension at subnoxious pressures in healthy volunteers and in irritable bowel syndrome (IBS) patients without alteration of colonic compliance. Asimadoline reduced satiation and enhanced the postprandial gastric volume (in female volunteers). However, there were no significant effects on gastrointestinal transit, colonic compliance, fasting or postprandial colonic tone. In a clinical trial in 40 patients with functional dyspepsia (Rome II), asimadoline did not significantly alter satiation or symptoms over 8 weeks. However, asimadoline, 0.5 mg, significantly decreased satiation in patients with higher postprandial fullness scores, and daily postprandial fullness severity (over 8 weeks); the asimadoline 1.0 mg group was borderline significant. In a clinical trial in patients with IBS, average pain 2 h post-on-demand treatment with asimadoline was not significantly reduced. Post hoc analyses suggest that asimadoline was effective in mixed IBS. In a 12-week study in 596 patients, chronic treatment with 0.5 mg and 1.0 mg asimadoline was associated with adequate relief of pain and discomfort, improvement in pain score and number of pain-free days in patients with IBS-D. The 1.0 mg dose was also efficacious in IBS-alternating. There were also weeks with significant reduction in bowel frequency and urgency. Asimadoline has been well tolerated in human trials to date.

The kappa-opioid receptor agonist asimadoline inhibits epithelial transport in mouse trachea and colon

The potent kappa-opioid receptor agonist n-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)-ethyl]-2,2-diphenyl-acetamide hydrochloride (asimadoline, EMD 61753) was initially developed for the treatment of chronic pain. Because opioids are well known to reduce secretion and to cause constipation, we investigated the effects on epithelial transport in murine trachea and colon. In Ussing chamber experiments, asimadoline (100 microM) decreased short-circuit currents in airways and colon epithelium. The inhibition of I(SC) was not blocked by naloxone (10 microM) or nor-binaltorphimine (10 microM), suggesting that the response was not mediated by kappa-opioid receptors. The effect of asimadoline on I(SC) was concentration-dependent with half-maximal inhibition of I SC at 23.7 (9.5-49.3) microM and was sensitive to the K+ channel blocker charybdotoxin (10 nM). The amiloride-sensitive Na+ current was reduced by asimadoline, but not in cAMP stimulated tissues. Asimadoline strongly inhibited transient Ca2+-dependent Cl- secretion, activated by the muscarinic receptor agonist carbachol (100 microM) or the purinergic agonist ATP (100 microM). Thus, asimadoline inhibits epithelial transport independent of kappa-opioid receptors, by inhibition of basolateral Ca2+-activated and charybdotoxin-sensitive K+ channels.