Behavioural and neurochemical effects of Ro 40-7592, a new COMT inhibitor with a potential therapeutic activity in Parkinson's disease (original) (raw)

Summary

Behavioural and some neurochemical effects of Ro 40-7592 (3,4-dihydroxy-4′-methyl-5-nitrobenzophenone), a new COMT inhibitor, were studied in rats and mice. Ro 40-7592 increased the effect of L-DOPA (plus benserazide) on locomotor activity, reserpine-induced hypothermia, and catalepsy induced by pimozide, haloperidol and fluphenazine. Locomotor hyperactivity induced by amphetamine or nomifensine, as well as stereotypy induced by amphetamine (but not apomorphine), were also increased by Ro 40-7592. The drug stimulated exploratory activity in the open field test. It decreased the levels of HVA and 3-MT, increased the level of DOPAC but did not change the levels of dopamine in the striatum, nucleus accumbens and frontal cortex. These results indicate that Ro 40-7592 may improve the therapy with L-DOPA (plus decarboxylase inhibitor) of Parkinson's disease.

Access this article

Log in via an institution

Subscribe and save

• Get 10 units per month
• Download Article/Chapter or eBook
• 1 Unit = 1 Article or 1 Chapter
• Cancel anytime Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

• Borgulya J, Bruderer H, Bernauer K, Zürcher G, Da Prada M (1989) Catechol-O-methyltransferase-inhibiting pyrocatechol derivatives: synthesis and structure-activity studies. Helv Chim Acta 72: 952–968
  Google Scholar
• Colzi A, Zürcher G, Da Prada M (1989) Plasma concentrations of endogenous DOPA and 3-O-methyl-DOPA in rats administered benserazide and carbidopa alone or in combination with the reversible COMT inhibitor Ro 41-0960. In: Przuntek H, Riederer P (eds) Early diagnosis and preventive therapy in Parkinson's disease. Springer, Wien New York, pp 191–196
  Google Scholar
• Delini-Stula A, Morpurgo C (1968) Influence of amphetamine and scopolamine on the catalepsy induced by diencephalic lesions in rats. Int J Neuropharmacol 7: 391–394
  Google Scholar
• Guldberg HC, Marsden CA (1975) Catechol-O-methyl transferase: pharmacological aspects and physiological role. Pharmacol Rev 27: 135–206
  Google Scholar
• Janssen PAJ, Jagenau AHM, Schellekens KHL (1960) Chemistry and pharmacology of compounds related to 4-(4-hydroxy-4-phenylpiperidino)-butyrophenone, part IV. Influence of haloperidol (R 1625) and of chlorpromazine on the behaviour of rats in an unfamiliar “open field” situation. Psychopharmacologia (Berlin) 1: 389–392
  Google Scholar
• Lindén I-B, Nissinen E, Etemadzadeh E, Kaakkola S, Männistö P, Pohto P (1988) Favorable effect of catechol-O-methyltransferase inhibition by OR-462 in experimental models of Parkinson's disease. J Pharmacol Exp Ther 247: 289–293
  Google Scholar
• Männistö PT, Kaakkola S (1989) New selective COMT inhibitors: useful adjuncts for Parkinson's disease. Trends Pharmacol Sci 10: 54–56
  Google Scholar
• Männistö PT, Kaakkola S, Nissinen E, Lindén I-B, Pohto P (1988) Properties of novel effective and highly selective inhibitors of catechol-O-methyltransferase. Life Sci 43: 1465–1471
  Google Scholar
• Muggli D, Zuercher G, Da Prada M (1989) Inhibition of COMT by Ro 40-7592, a potential drug for Parkinson's disease therapy. 12th Annual Meeting ENA, Torino, September 3–7, 1989
• Nissinen E, Lindén I-B, Schultz E, Kaakkola S, Männistö PT, Pohto P (1988) Inhibition of catechol-O-methyltransferase activity by two novel disubstituted catechols in the rats. Eur J Pharmacol 153: 263–269
  Google Scholar
• Reches A, Mielke LR, Fahn S (1982) 3-O-Methyldopa inhibits rotations induced by levodopa in rats after unilateral destruction of the nigrostriatal pathway. Neurology 32: 887–888
  Google Scholar
• Zürcher G, Keller HH, Bruderer H, Borgulya J, Da Prada M (1988) Caratteristiche neurochimiche di una nuova classe di inhibitori della COMT attivi per via orale: livelli plasmatici di DOPA e 3-OMD nel ratto trattato con DOPA e benserazide. In: Agnoli A, Battistin L (eds) Morbi di Parkinson e demenze: metodologie diagnostiche. Pubbl D Guanella, Roma, pp. 15–29
  Google Scholar
• Zürcher G, Colzi A, Da Prada M (1989a) Marked improvement of DOPA bioavailability in rats by Ro 40-7592, a novel, orally active COMT inhibitor. International Basal Ganglia Society, Third Triennial Meeting, Capo Boi, Cagliari, June 10–13, 1989
• Zürcher G, Keller HH, Kettler R, Borgulya J, Bonetti EP, Eigenmann R, Da Prada M (1989b) Ro 40-7592, a novel, very potent and orally active inhibitor of catechol-O-methyltransferase: a pharmacological study in rats. In: Parkinsons disease: anatomy, pathology and therapy (Adv Neurol 53: 497–502)

Download references

Author information

Author notes

1. J. Maj
   Present address: Institute of Pharmacology, Polish Academy of Sciences, Smetna Street 12, PL 31-343, Kraków, Poland

Authors and Affiliations

1. Institute of Pharmacology, Polish Academy of Sciences, Smetna Street 12, PL 31-343, Kraków, Poland
   Z. Rogóż, G. Skuza, H. Sowińska & J. Superata

Authors

1. J. Maj
   You can also search for this author inPubMed Google Scholar
2. Z. Rogóż
   You can also search for this author inPubMed Google Scholar
3. G. Skuza
   You can also search for this author inPubMed Google Scholar
4. H. Sowińska
   You can also search for this author inPubMed Google Scholar
5. J. Superata
   You can also search for this author inPubMed Google Scholar

Rights and permissions

About this article

Cite this article

Maj, J., Rogóż, Z., Skuza, G. et al. Behavioural and neurochemical effects of Ro 40-7592, a new COMT inhibitor with a potential therapeutic activity in Parkinson's disease.J Neural Transm Gen Sect 2, 101–112 (1990). https://doi.org/10.1007/BF02260898

Download citation

• Received: 22 December 1989
• Accepted: 31 January 1990
• Issue Date: June 1990
• DOI: https://doi.org/10.1007/BF02260898

Keywords