Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1985 Oct;86(2):357–366. doi: 10.1111/j.1476-5381.1985.tb08904.x

Evaluation of the muscle relaxant properties of a novel beta-carboline, ZK 93423 in rats and cats.

T Klockgether, I Pardowitz, M Schwarz, K H Sontag, L Turski
PMCID: PMC1916712  PMID: 3931731

Abstract

The muscle relaxant action of ZK 93423 (6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate ethyl ester), a novel beta-carboline with agonistic properties at the benzodiazepine receptor, was examined by assessing its effect on the tonic electromyogram (EMG) activity of the gastrocnemiussoleus (GS) muscle of genetically spastic rats and on ventral root reflexes, presynaptic inhibition and fusimotor activity in the spinal cord of decerebrate cats. ZK 93423 (0.1-10.0 mg kg-1) depressed the tonic EMG activity in mutant rats in a dose-dependent manner. This effect was reversed by the benzodiazepine antagonist Ro 15-1788 (5.0 mg kg-1). Both ZK 93423 (0.5 mg kg-1) and diazepam (0.3 mg kg-1) enhanced the presynaptic inhibition of the GS muscle and associated dorsal root potentials in decerebrate cats in an almost identical manner. The actions of both drugs were reversed by Ro 15-1788 (5.0 mg kg-1). ZK 93423 (0.5 mg kg-1) and diazepam (0.3 mg kg-1) depressed the activity of both static and dynamic fusimotor neurones, as deduced from changes in the afferent responses of muscle spindle primary endings to low frequency (1 s-1) sinusoidal stretching. The depressant action of diazepam (0.3 mg kg-1) was weaker than that of ZK 93423 (0.5 mg kg-1). The actions of both drugs were reversed by Ro 15-1788 (5.0 mg kg-1). ZK 93423 (0.5 mg kg-1) failed to alter the magnitude of monosynaptic ventral root reflexes evoked by electrical stimulation of a flexor and an extensor nerve, whereas diazepam (0.3 mg kg-1) had a depressant effect on both types of monosynaptic reflexes, which was antagonized by Ro 15-1788 (5.0 mg kg-1). Neither ZK 93423 (0.5 mg kg-1) nor diazepam (0.3 mg kg-1) depressed polysynaptic ventral root reflexes evoked by electrical stimulation of a flexor and a cutaneous nerve. The present results demonstrate that ZK 93423 exerts a potent muscle relaxant action due to a specific interaction with benzodiazepine receptors. However, its profile of actions on spinal motor mechanisms is not identical to that of diazepam.

Full text

PDF
357

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Biscoe T. J., Fry J. P. Some pharmacological studies on the spastic mouse. Br J Pharmacol. 1982 Jan;75(1):23–35. doi: 10.1111/j.1476-5381.1982.tb08754.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Braestrup C., Nielsen M., Olsen C. E. Urinary and brain beta-carboline-3-carboxylates as potent inhibitors of brain benzodiazepine receptors. Proc Natl Acad Sci U S A. 1980 Apr;77(4):2288–2292. doi: 10.1073/pnas.77.4.2288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cowen P. J., Green A. R., Nutt D. J. Ethyl beta-carboline carboxylate lowers seizure threshold and antagonizes flurazepam-induced sedation in rats. Nature. 1981 Mar 5;290(5801):54–55. doi: 10.1038/290054a0. [DOI] [PubMed] [Google Scholar]
  4. Crankshaw D. P., Raper C. Mephenesin, methocarbamol, chlordiazepoxide and diazepam: actions on spinal reflexes and ventral root potentials. Br J Pharmacol. 1970 Jan;38(1):148–156. doi: 10.1111/j.1476-5381.1970.tb10343.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Croucher M., De Sarro G., Jensen L., Meldrum B. Behavioural and convulsant actions of two methyl esters of beta-carboline-3-carboxylic acid in photosensitive baboons and in DBA/2 mice. Eur J Pharmacol. 1984 Sep 3;104(1-2):55–60. doi: 10.1016/0014-2999(84)90368-6. [DOI] [PubMed] [Google Scholar]
  6. File S. E., Lister R. G., Nutt D. J. The anxiogenic action of benzodiazepine antagonists. Neuropharmacology. 1982 Oct;21(10):1033–1037. doi: 10.1016/0028-3908(82)90118-6. [DOI] [PubMed] [Google Scholar]
  7. Goodwin G. M., Hulliger M., Matthews P. B. The effects of fusimotor stimulation during small amplitude stretching on the frequency-response of the primary ending of the mammalian muscle spindle. J Physiol. 1975 Dec;253(1):175–206. doi: 10.1113/jphysiol.1975.sp011186. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hudson R. D., Wolpert M. K. Central muscle relaxant effects of diazepam. Neuropharmacology. 1970 Sep;9(5):481–488. doi: 10.1016/0028-3908(70)90021-3. [DOI] [PubMed] [Google Scholar]
  9. Hulliger M., Matthews P. B., Noth J. Effects of combining static and dynamic fusimotor stimulation on the response of the muscle spindle primary ending to sinusoidal stretching. J Physiol. 1977 Jun;267(3):839–856. doi: 10.1113/jphysiol.1977.sp011840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hulliger M., Matthews P. B., Noth J. Static and dynamic fusimotor action on the response of Ia fibres to low frequency sinusoidal stretching of widely ranging amplitude. J Physiol. 1977 Jun;267(3):811–838. doi: 10.1113/jphysiol.1977.sp011839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hunkeler W., Möhler H., Pieri L., Polc P., Bonetti E. P., Cumin R., Schaffner R., Haefely W. Selective antagonists of benzodiazepines. Nature. 1981 Apr 9;290(5806):514–516. doi: 10.1038/290514a0. [DOI] [PubMed] [Google Scholar]
  12. Jensen L. H., Marescaux C., Vergnes M., Micheletti G., Petersen E. N. Antiepileptic action of the beta-carboline ZK 91296 in a genetic petit mal model in rats. Eur J Pharmacol. 1984 Jul 20;102(3-4):521–524. doi: 10.1016/0014-2999(84)90574-0. [DOI] [PubMed] [Google Scholar]
  13. Jensen L. H., Petersen E. N., Braestrup C., Honoré T., Kehr W., Stephens D. N., Schneider H., Seidelmann D., Schmiechen R. Evaluation of the beta-carboline ZK 93 426 as a benzodiazepine receptor antagonist. Psychopharmacology (Berl) 1984;83(3):249–256. doi: 10.1007/BF00464789. [DOI] [PubMed] [Google Scholar]
  14. Klockgether T., Schwarz M., Turski L., Sontag K. H. ZK 91296, an anticonvulsant beta-carboline which lacks muscle relaxant properties. Eur J Pharmacol. 1985 Apr 16;110(3):309–315. doi: 10.1016/0014-2999(85)90557-6. [DOI] [PubMed] [Google Scholar]
  15. McDonald T. J., Fox J. E. Effects of porcine gastrin releasing peptide (GRP) on canine antral motility and gastrin release in vivo. Life Sci. 1984 Sep 24;35(13):1415–1422. doi: 10.1016/0024-3205(84)90400-4. [DOI] [PubMed] [Google Scholar]
  16. Meldrum B. S., Evans M. C., Braestrup C. Anticonvulsant action in the photosensitive baboon, Papio papio, of a novel beta-carboline derivative, ZK 91296. Eur J Pharmacol. 1983 Jul 22;91(2-3):255–259. doi: 10.1016/0014-2999(83)90474-0. [DOI] [PubMed] [Google Scholar]
  17. Möhler H., Okada T. Benzodiazepine receptor: demonstration in the central nervous system. Science. 1977 Nov 25;198(4319):849–851. doi: 10.1126/science.918669. [DOI] [PubMed] [Google Scholar]
  18. Nutt D. J., Cowen P. J., Little H. J. Unusual interactions of benzodiazepine receptor antagonists. Nature. 1982 Feb 4;295(5848):436–438. doi: 10.1038/295436a0. [DOI] [PubMed] [Google Scholar]
  19. Petersen E. N., Jensen L. H., Honoré T., Braestrup C. Differential pharmacological effects of benzodiazepine receptor inverse agonists. Adv Biochem Psychopharmacol. 1983;38:57–64. [PubMed] [Google Scholar]
  20. Petersen E. N., Jensen L. H., Honoré T., Braestrup C., Kehr W., Stephens D. N., Wachtel H., Seidelman D., Schmiechen R. ZK 91296, a partial agonist at benzodiazepine receptors. Psychopharmacology (Berl) 1984;83(3):240–248. doi: 10.1007/BF00464788. [DOI] [PubMed] [Google Scholar]
  21. Petersen E. N., Jensen L. H. Proconflict effect of benzodiazepine receptor inverse agonists and other inhibitors of GABA function. Eur J Pharmacol. 1984 Aug 3;103(1-2):91–97. doi: 10.1016/0014-2999(84)90193-6. [DOI] [PubMed] [Google Scholar]
  22. Polc P., Bonetti E. P., Schaffner R., Haefely W. A three-state model of the benzodiazepine receptor explains the interactions between the benzodiazepine antagonist Ro 15-1788, benzodiazepine tranquilizers, beta-carbolines, and phenobarbitone. Naunyn Schmiedebergs Arch Pharmacol. 1982 Dec;321(4):260–264. doi: 10.1007/BF00498510. [DOI] [PubMed] [Google Scholar]
  23. Polc P., Laurent J. P., Scherschlicht R., Haefely W. Electrophysiological studies on the specific benzodiazepine antagonist Ro 15-1788. Naunyn Schmiedebergs Arch Pharmacol. 1981 Jul;316(4):317–325. doi: 10.1007/BF00501364. [DOI] [PubMed] [Google Scholar]
  24. Polc P., Möhler H., Haefely W. The effect of diazepam on spinal cord activities: possible sites and mechanisms of action. Naunyn Schmiedebergs Arch Pharmacol. 1974;284(4):319–337. doi: 10.1007/BF00504702. [DOI] [PubMed] [Google Scholar]
  25. Prado de Carvalho L., Grecksch G., Cavalheiro E. A., Dodd R. H., Chapouthier G., Rossier J. Characterization of convulsions induced by methyl beta-carboline-3-carboxylate in mice. Eur J Pharmacol. 1984 Aug 17;103(3-4):287–293. doi: 10.1016/0014-2999(84)90489-8. [DOI] [PubMed] [Google Scholar]
  26. Przybyla A. C., Wang S. C. Locus of central depressant action of diazepam. J Pharmacol Exp Ther. 1968 Oct;163(2):439–447. [PubMed] [Google Scholar]
  27. Schmidt R. F., Vogel M. E., Zimmermann M. Die Wirkung von Diazepam auf die präsynaptische Hemmung und andere Rückenmarksreflexe. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol. 1967;258(1):69–82. [PubMed] [Google Scholar]
  28. Schwarz M., Turski L., Janiszewski W., Sontag K. H. Is the muscle relaxant effect of diazepam in spastic mutant rats mediated through GABA-independent benzodiazepine receptors? Neurosci Lett. 1983 Apr 11;36(2):175–180. doi: 10.1016/0304-3940(83)90261-6. [DOI] [PubMed] [Google Scholar]
  29. Schwarz M., Turski L., Sontag K. H. Reversal of the muscle relaxant effect of diazepam but not of progabide by a specific benzodiazepine antagonist: Ro 15-1788. Eur J Pharmacol. 1983 May 20;90(1):139–142. doi: 10.1016/0014-2999(83)90226-1. [DOI] [PubMed] [Google Scholar]
  30. Squires R. F., Brastrup C. Benzodiazepine receptors in rat brain. Nature. 1977 Apr 21;266(5604):732–734. doi: 10.1038/266732a0. [DOI] [PubMed] [Google Scholar]
  31. Stephens D. N., Shearman G. T., Kehr W. Discriminative stimulus properties of beta-carbolines characterized as agonists and inverse agonists at central benzodiazepine receptors. Psychopharmacology (Berl) 1984;83(3):233–239. doi: 10.1007/BF00464787. [DOI] [PubMed] [Google Scholar]
  32. Stratten W. P., Barnes C. D. Diazepam and presynaptic inhibition. Neuropharmacology. 1971 Nov;10(6):685–696. doi: 10.1016/0028-3908(71)90083-9. [DOI] [PubMed] [Google Scholar]
  33. Swinyard E. A., Castellion A. W. Anticonvulsant properties of some benzodiazepines. J Pharmacol Exp Ther. 1966 Mar;151(3):369–375. [PubMed] [Google Scholar]
  34. Takano K., Student J. C. Effect of diazepam on the gamma motor system indicated by the responses of the muscle spindle of the triceps surae muscle of the decerebrate cat to the muscle stretch. Naunyn Schmiedebergs Arch Pharmacol. 1978 Mar;302(1):91–101. doi: 10.1007/BF00586603. [DOI] [PubMed] [Google Scholar]
  35. Tenen S. S., Hirsch J. D. beta-Carboline-3-carboxylic acid ethyl ester antagonizes diazepam activity. Nature. 1980 Dec 11;288(5791):609–610. doi: 10.1038/288609a0. [DOI] [PubMed] [Google Scholar]
  36. Tseng T. C., Wang S. C. Locus of action of centrally acting muscle relaxants, diazepam and tybamate. J Pharmacol Exp Ther. 1971 Aug;178(2):350–360. [PubMed] [Google Scholar]
  37. Turski L., Schwarz M., Sontag K. H. Interaction between phenytoin and diazepam in mutant Han-Wistar rats with progressive spastic paresis. Naunyn Schmiedebergs Arch Pharmacol. 1982 Oct;321(1):48–51. doi: 10.1007/BF00586348. [DOI] [PubMed] [Google Scholar]
  38. Turski L., Schwarz M., Turski W. A., Ikonomidou C., Sontag K. H. Effect of aminophylline on muscle relaxant action of diazepam and phenobarbitone in genetically spastic rats: further evidence for a purinergic mechanism in the action of diazepam. Eur J Pharmacol. 1984 Aug 3;103(1-2):99–105. doi: 10.1016/0014-2999(84)90194-8. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES