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Journal of Pharmacology and Experimental Therapeutics

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OtherDRUG METABOLISM AND DISPOSITION

8-Alkylamino-Substituted Analogs of N6-Cyclopentyladenosine Are Partial Agonists for the Cardiovascular Adenosine A1 Receptors in Vivo

E. A. Van Schaick, R. A. A. Mathôt, J. M. Gubbens-Stibbe, M. W. E. Langemeijer, H. C. P. F. Roelen, A. P. Ijzerman and M. Danhof
Journal of Pharmacology and Experimental Therapeutics November 1997, 283 (2) 800-808;
E. A. Van Schaick
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R. A. A. Mathôt
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J. M. Gubbens-Stibbe
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M. W. E. Langemeijer
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H. C. P. F. Roelen
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A. P. Ijzerman
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M. Danhof
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Abstract

Partial adenosine A1 receptor agonists with reduced intrinsic activity at the cardiovascular system would be promising for therapeutic application (e.g., as antilipolytic agents). In the present study a series of 8-alkylamino [methyl (M)-, ethyl (E)-, propyl (P)-, butyl (B)- and cyclopentyl (CP)-] derivatives of N6-cyclopentyladenosine (CPA) were investigated in conscious normotensive rats. After intravenous administration of the compounds to rats, heart rate (HR) and mean arterial pressure were monitored continuously, and serial arterial blood samples were drawn for determination of the pharmacokinetics. The concentration-heart rate relationships of the compounds were described on the basis of an integrated pharmacokinetic-pharmacodynamic model. The blood concentration-time profiles of the compounds could be described best by a biexponential function. The derivatives of CPA had uniform pharmacokinetic properties. The larger volume of distribution at steady state of the 8-substituted analogs resulted in terminal half-lives (ranging from 17 to 24 min) which were significantly longer than for CPA (7 min). All derivatives of CPA produced less pronounced reductions in HR and MAP than CPA. The relationship between concentration and the reduction in HR was adequately described by the sigmoidalEmax model in individual rats given 8MCPA, 8ECPA and 8PCPA. 8BCPA and 8CPCPA were nearly inactive on heart rate. The in vivo EC50,u values for the reduction in HR (366 nM, 210 nM, 170 nM and 175 nM for 8MCPA, 8ECPA, 8PCPA and 8BCPA, respectively) were in the same order of magnitude as the affinities in receptor binding studies. The order of magnitude of the intrinsic activities (Emax) was CPA > 8MCPA > 8ECPA = 8PCPA > 8BCPA > 8CPCPA, which indicated partial agonism of the compounds in vivo. Thein vivo parameter Emaxcorrelated highly (r = 0.97) to the GTP shift observed in radioligand binding experiments.

Footnotes

  • Send reprint requests to: Prof. Meindert Danhof, Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Sylvius Laboratories, P.O. Box 9503, 2300 RA Leiden, The Netherlands.

  • ↵1 This work was financed partially by a grant from Glaxo Wellcome, United Kingdom.

  • Abbreviations:
    CPA
    N6-cyclopentyladenosine
    8MCPA
    8-(methylamino)-CPA
    8ECPA
    8-(ethylamino)-CPA
    8PCPA
    8-(propylamino)-CPA
    8BCPA
    8-(butylamino)-CPA
    8CPCPA
    8-(cyclopentylamino)-CPA
    DCCA
    1-deaza-2-chloro-N6-cyclopentyladenosine
    DPCPX
    1,3-dipropyl-8-cyclopentylxanthine
    GTP
    guanosine 5′-triphosphate
    HPLC
    high-pressure liquid chromatography
    P/B
    plasma-to-blood ratio
    fu
    fraction unbound
    EC50,u
    EC50based on free drug concentrations
    HR
    heart rate
    MAP
    mean arterial pressure
    ANOVA
    analysis of variance
    PK/PD
    pharmacokinetic-pharmacodynamic
    • Received January 27, 1997.
    • Accepted July 21, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 283, Issue 2
1 Nov 1997
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OtherDRUG METABOLISM AND DISPOSITION

8-Alkylamino-Substituted Analogs of N6-Cyclopentyladenosine Are Partial Agonists for the Cardiovascular Adenosine A1 Receptors in Vivo

E. A. Van Schaick, R. A. A. Mathôt, J. M. Gubbens-Stibbe, M. W. E. Langemeijer, H. C. P. F. Roelen, A. P. Ijzerman and M. Danhof
Journal of Pharmacology and Experimental Therapeutics November 1, 1997, 283 (2) 800-808;

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OtherDRUG METABOLISM AND DISPOSITION

8-Alkylamino-Substituted Analogs of N6-Cyclopentyladenosine Are Partial Agonists for the Cardiovascular Adenosine A1 Receptors in Vivo

E. A. Van Schaick, R. A. A. Mathôt, J. M. Gubbens-Stibbe, M. W. E. Langemeijer, H. C. P. F. Roelen, A. P. Ijzerman and M. Danhof
Journal of Pharmacology and Experimental Therapeutics November 1, 1997, 283 (2) 800-808;
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