Agents and Actions

, Volume 12, Issue 5, pp 684–690 | Cite as

The analgesic and anti-inflammatory profile of (±)-5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2a]pyrrole-1-carboxylic acid (RS-37619)

  • W. H. RooksII
  • A. J. Tomolonis
  • P. J. Maloney
  • M. B. Wallach
  • M. E. Schuler
Immunosuppression and Inflammation

Abstract

RS-37619 showed highly potent analgesic activity when given p.o. in tests utilizing underlying inflammation. It inhibited phenylquinone-induced writhing in the mouse and rat (350 and 180×aspirin respectively) and the pain induced by flexing the adjuvant-inflamed rat paw (∼ 800×aspirin). The agent increased the pain threshold of compressed yeast-inflamed rat paws (3–10 ×naproxen). RS-37619 did not increase the pain threshold of the noninflamed paw and was inactive in the mouse hot plate test; therefore it is probably not a centrally acting or morphinelike agent. RS-37619 was also highly active p.o. in rat models of acute and chronic inflammation. It inhibited carrageenan-induced paw edema (36×phenylbutazone), cotton pellet-induced granuloma (≤1×indomethacin) and in an 18-day test, prevented the development of adjuvant-induced arthritis (∼2×naproxen). RS-37619 exhibited antiphlogistic activity in adrenalectomized rats. It did not have corticosteroid activity. When given p.o., RS-37619 lowered yeast-induced pyrexia (20×aspirin). Gastro-intestinal irritation was seen in the rat with doses ≥6.4 mg/kg/day p.o. The agent elicited mild CNS and cardiovascular activity only at doses far in excess of those required for analgesic and anti-inflammatory activity.

Keywords

Naproxen Pain Threshold Phenylbutazone Underlying Inflammation Potent Analgesic Activity 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. [1]
    F. Franco, R. Greenhouse andJ. Muchowski,Novel syntheses of 5-aroyl-1,2-dihydro-3H-pyrollo-[1,2a]pyrolle-1-carboxylic acids, J. org. Chem. (in Press, Vol. 47, 1982).Google Scholar
  2. [2]
    W.H. Rooks II, A.J. Tomolonis, P.J. Maloney, A. Roszkowski andM.B. Wallach,The antiinflammatory and analgesic profile of 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetic acid (tiopinac), Agents and Actions10, 266–273 (1980).PubMedGoogle Scholar
  3. [3]
    L.C. Hendershot andJ. Forsaith,Antagonism of the frequency of phenylquinone-induced writhing in the mouse by weak analgesics and nonanalgesics, J. Pharmac. exp. Ther.125, 237–240 (1959).Google Scholar
  4. [4]
    L.O. Randall andJ.J. Selitto,A method for measurement of analgesic activity of inflamed tissue, Archs int. Pharmacodyn. Ther.111, 409–419 (1957).Google Scholar
  5. [5]
    S. Kazuna andK. Kawai,Evaluation of analgesic agents in rats with adjuvant arthritis, Chem. pharm. Bull.23, 1184–1191 (1975).PubMedGoogle Scholar
  6. [6]
    P.A.J. Janssen andP. Jageneau,A new series of potent analgesics: dextro 2∶2-diphenyl-3-methyl-4-morpholinobutyrylpyrrolidine and related amides. Part 1. Chemical structure in pharmacological activity, J. Pharm. Pharmac.9, 381–400 (1957).Google Scholar
  7. [7]
    C.A. Winter, E.A. Risley andG.W. Nuss,Carrageenan-induced edema in hind paw of the rat as an assay for anti-inflammatory drugs, Proc. Soc. exp. Biol. Med.111, 544–547 (1962).Google Scholar
  8. [8]
    R. Meier, W. Schuler andP. Desaulles,Zur Frage des Mechanismus der Hemmung des Bindegewebswachstums durch Cortisone, Experientia (Basel)6, 469–471 (1950).Google Scholar
  9. [9]
    C.M. Pearson,Development of arthritis periarthritis and periostitis in rats given adjuvants, Proc. Soc. exp. Biol. Med.91, 95–101 (1956).PubMedGoogle Scholar
  10. [10]
    A.P. Roszkowski, W.H. Rooks II, A.J. Tomolonis andL.M. Miller,Anti-inflammatory and analgesic properties of d-2-(6′-methoxy-2′-naphthyl)-propionic acid (naproxen), J. Pharmac. exp. Ther.179, 114–123 (1971).Google Scholar
  11. [11]
    S. Irwin, Drug screening and evaluation of new compounds in animals. InAnimal and Clinical Pharmacological Techniques in Drug Evaluation (EdsJ.H. Nodine andP.E. Siegler). Year Book Medical Publishers, Chicago 1964.Google Scholar
  12. [12]
    E.A. Swinyard, W.C. Brown andL.S. Goodman,Comparative assays of antiepileptic drugs in mice and rats, J. Pharmac. exp. Ther.106, 319–330 (1952).Google Scholar
  13. [13]
    D.J. Finney,Statistical Methods in Biological Assay, Hafner Publishing Co., New York 1964.Google Scholar
  14. [14]
    W.H. Rooks II, A.J. Tomolonis, P.J. Maloney, M.B. Wallach andM.E. Schuler,The analgesic and anti-inflammatory profile of (±)-5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2a]pyrrole-1-carboxylic acid (RS-37619),Fedn Proc. 38, 440 (1979).Google Scholar

Copyright information

© Birkhäuser Verlag 1982

Authors and Affiliations

  • W. H. RooksII
    • 1
  • A. J. Tomolonis
    • 1
  • P. J. Maloney
    • 1
  • M. B. Wallach
    • 1
  • M. E. Schuler
    • 1
  1. 1.Department of Bioassay and PharmacologySyntex (USA) Inc., Research DivisionPalo AltoUSA

Personalised recommendations