Vol. 283, Issue 2, 800-808, 1997

8-Alkylamino-Substituted Analogs of N⁶-Cyclopentyladenosine Are Partial Agonists for the Cardiovascular Adenosine A₁ Receptors in Vivo¹

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

Divisions of Pharmacology (E.S., R.M., J.G.-S., M.D.) and Medicinal Chemistry (H.R., A.IJ.), Leiden/Amsterdam Center for Drug Research, Leiden University, 2300 RA, Leiden, The Netherlands

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 sigmoidal E_max model in individual rats given 8MCPA, 8ECPA and 8PCPA. 8BCPA and 8CPCPA were nearly inactive on heart rate. The in vivo EC_50,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 (E_max) was CPA > 8MCPA > 8ECPA = 8PCPA > 8BCPA > 8CPCPA, which indicated partial agonism of the compounds in vivo. The in vivo parameter E_max correlated highly (r = 0.97) to the GTP shift observed in radioligand binding experiments.