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

British Journal of Pharmacology - Tập 113 Số 4 - Trang 1317-1327 - 1994
Andrew Barber1, Gerd D. Bartoszyk1, H.M. Bender2, Rudolf Gottschlich1, Hartmut E. Greiner1, J. Harting1, Frank Mauler1, Klaus-Otto Minck1, Robert Murray1, Maxime Simon3, Christoph A. Seyfried1
1Preclinical Pharmaceutical Research, E. Merck, 64271 Darmstadt, Germany
2Institute of Pharmacokinetics and Metabolism, E. Merck, 85567 Grafing, Germany
3Merck-Clevenot S.A., 5/9 Rue Anquetil, F-94731 Nogent-sur-Marne, France

Tóm tắt

The pharmacological properties of the novel diarylacetamide k‐opioid receptor agonist, EMD 61753, have been compared with those of ICI 197067 (a centrally‐acting k agonist) and ICI204448 (a peripherally‐selective k agonist). EMD 61753 binds with high affinity (IC50 5.6 nm) and selectivity (k:μ:δ:σ binding ratio 1:536: 125: > 1,786) to k‐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). 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. 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 30mg kg−1, s.c., (doses of 0.1, 1.0 and 10mg 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. 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 μg) into the inflamed tissue, a result which indicates that this opioid effect is mediated peripherally. Cutaneous plasma protein extravasation produced by antidromic electrical stimulation of the rat saphenous nerve was dose‐dependently inhibited by systemically‐applied EMD 61753 (ID50 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 μg). Extravasation elicited by the intraplantar application of substance P (10 μg) was not influenced by the administration of EMD 61753. EMD 61753 produced dose‐dependent diuresis in non‐hydrated rats at doses of and above 10 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. 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 (lO mg 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. The present experiments therefore indicate that EMD 61753 is a potent, selective and orally‐effective full K‐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.

Từ khóa


Tài liệu tham khảo

10.1016/0014-2999(93)90233-8

10.1111/j.1476-5381.1994.tb14815.x

BARBER A., 1993, In vivo effects of the peripherally‐selective, orally‐active, k‐opioid receptor agonist EMD 61753, Soc. Neurosci. Abstr., 19, 577.15

10.1002/med.2610120505

10.1111/j.1476-5381.1981.tb10425.x

BROOKS D.P., 1993, Opiate receptors within the blood‐brain barrier mediate kappa agonist‐induced water diuresis, J. Pharmacol. Exp. Ther., 266, 164

10.1016/0014-2999(88)90546-8

DAMAS J., 1978, Inhibition de l'áction hypotensive de l'ácide arachidonique chez le rat, J. Pharmacol. (Paris), 9, 13

10.1073/pnas.85.14.5274

DIXON W.J., 1948, A method for obtaining and analyzing sensitivity data, J. Am. Stat. Ass., 43, 109, 10.1080/01621459.1948.10483254

DYKSTRA L.A., 1987, Kappa opioids in Rhesus monkeys. I. Diuresis, sedation, analgesia and discriminative stimulus effects, J. Pharmacol. Exp. Ther., 242, 413

10.1111/j.1476-5381.1988.tb11408.x

GOTTSCHLICH R., 1993, EMD 61753 is a unique representative of the diarylacetamides, a novel class of k‐opiate agonists, Soc. Neurosci. Abstr., 19, 577.14

10.1016/0014-2999(90)94178-Z

HAYES A.G., 1988, Can the mouse abdominal constriction test be used as a model for peripheral opioid antinociceptive activity?, Br. J. Pharmacol., 93, 173P

10.1016/0304-3959(87)90088-1

KUSCHINSKY G., 1981, Kurzes Lehrbuch der Pharmakologie und Toxikologie

10.1016/0014-2999(85)90431-5

10.1007/BF00500282

LITCHFIELD J.T., 1949, A simplified method of evaluating dose‐effect experiments, J. Pharmacol. Exp. Ther., 96, 99

MANZANARES J., 1991, Kappa opioid receptor‐mediated regulation of dopaminergic neurons in rat brain, J. Pharmacol. Exp. Ther., 256, 500

MEßLINGER K., 1993, Abstract 42 7th World Congress on Pain, Paris

10.1358/dof.1990.015.07.127736

10.1016/0165-6147(87)90192-1

10.1016/B978-0-12-547620-1.50007-2

PETERS G., 1989, Human central nervous system effects of a selective kappa opioid agonist, Clin. Pharmacol. Ther., 51, PPF‐5

PETERS G.R., 1987, Diuretic actions in man of a selective kappa opioid agonist: U‐62,066E, J. Pharmacol. Exp. Ther., 240, 128

10.1126/science.3016896

REECE P.A., 1989, Dose proportionality and pharmacodynamics of intramuscular CI–977, Clin. Pharmacol. Ther., 51, PIII

10.1016/0166-2236(90)90043-A

10.1111/j.1476-5381.1992.tb14413.x

ROSSI N.F., 1993, Kappa agonist BRL 52656 inhibits osmotically‐stimulated vasopressin secretion preferentially at hypothalamic sites, Soc. Neurosci. Abstr., 19, 478.9

10.1016/0304-3940(87)90201-1

10.1073/pnas.91.1.68

10.1002/bmc.1130010206

10.1111/j.1476-5381.1989.tb11911.x

SHIPPENBERG T.S., 1993, Examination of the neurochemical substrates mediating the motivational effects of opioids: role of the mesolimbic dopamine system and D‐1 vs. D‐2 dopamine receptors, J. Pharmacol. Exp. Ther., 265, 53

SMITH T.W., 1985, Antinociceptive models displaying peripheral opioid activity, Int. J. Tiss. Reac., 7, 61

10.1111/j.1471-4159.1990.tb04963.x

10.1213/00000539-199301000-00031

10.1016/0167-0115(92)90068-6

Thông tin
Thông tin xuất bản

British Journal of Pharmacology

Tập 113 Số 4

1317-1327

Thông tin tác giả