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3-Halo-5,7-dimethylpyrazolo [1,5-a]pyrimidines, a nonbenzodiazepinoid class of antianxiety agents devoid of potentiation of central nervous system depressant effects of ethanol or barbiturates.

Publication ,  Journal Article
Kirkpatrick, WE; Okabe, T; Hillyard, IW; Robins, RK; Dren, AT; Novinson, T
Published in: Journal of medicinal chemistry
March 1977

Forty derivatives (1-40) of pyrazolo[1,5-a]pyrimidine were synthesized and evaluated for antianxiety properties via gross behavioral observations in rats. Five of these compounds, including 5,7-dimethylpyrazolo[1,5-a]pyrimidine (6) and the 3-fluoro (7), 3-chloro (8), 3-bromo (9), and 3-iodo (10) derivatives, were selected for advanced evaluation. Although 6 and 7 had marginal activity, 8-10 had an anxiolytic effect in animals comparable to the clinically useful benzodiazepines, diazepam, and chlorodiazepoxide. Comparison with chlorpromazine indicated that 6-10 are probably not antipsychotic agents. These compounds also lacked activity in anticonvulsant and analgesic tests. Acute toxicity data (mouse, ip and po) indicated that 8-10 had excellent therapeutic ratios, although 10 was more poorly absorbed than 8 and 9. Further demonstration of anxiolytic efficacy was obtained by comparing the effects of 8 and 9 with the benzodiazepines in modifying provoked aggression in monkeys, rats (muricide), and fighting mice. The most remarkable observation, however, was that 8 and 9 had no effect, at the anxiolytic threshold, in potentiating the CNS depressant effects of ethanol or sodium barbital (po) in treated mice. In contrast, diazepam and chlorodiazepoxide potentiated this drug interaction effect at minimal anxiolytic doses.

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Published In

Journal of medicinal chemistry

DOI

EISSN

1520-4804

ISSN

0022-2623

Publication Date

March 1977

Volume

20

Issue

3

Start / End Page

386 / 393

Related Subject Headings

  • Rats
  • Pyrimidines
  • Muscle Relaxants, Central
  • Motor Activity
  • Mice
  • Methods
  • Medicinal & Biomolecular Chemistry
  • Male
  • Macaca mulatta
  • Lethal Dose 50
 

Citation

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Kirkpatrick, W. E., Okabe, T., Hillyard, I. W., Robins, R. K., Dren, A. T., & Novinson, T. (1977). 3-Halo-5,7-dimethylpyrazolo [1,5-a]pyrimidines, a nonbenzodiazepinoid class of antianxiety agents devoid of potentiation of central nervous system depressant effects of ethanol or barbiturates. Journal of Medicinal Chemistry, 20(3), 386–393. https://doi.org/10.1021/jm00213a014
Kirkpatrick, W. E., T. Okabe, I. W. Hillyard, R. K. Robins, A. T. Dren, and T. Novinson. “3-Halo-5,7-dimethylpyrazolo [1,5-a]pyrimidines, a nonbenzodiazepinoid class of antianxiety agents devoid of potentiation of central nervous system depressant effects of ethanol or barbiturates.Journal of Medicinal Chemistry 20, no. 3 (March 1977): 386–93. https://doi.org/10.1021/jm00213a014.
Kirkpatrick, W. E., et al. “3-Halo-5,7-dimethylpyrazolo [1,5-a]pyrimidines, a nonbenzodiazepinoid class of antianxiety agents devoid of potentiation of central nervous system depressant effects of ethanol or barbiturates.Journal of Medicinal Chemistry, vol. 20, no. 3, Mar. 1977, pp. 386–93. Epmc, doi:10.1021/jm00213a014.
Journal cover image

Published In

Journal of medicinal chemistry

DOI

EISSN

1520-4804

ISSN

0022-2623

Publication Date

March 1977

Volume

20

Issue

3

Start / End Page

386 / 393

Related Subject Headings

  • Rats
  • Pyrimidines
  • Muscle Relaxants, Central
  • Motor Activity
  • Mice
  • Methods
  • Medicinal & Biomolecular Chemistry
  • Male
  • Macaca mulatta
  • Lethal Dose 50