A1 adenosine receptor agonists with reduced intrinsic activity may be therapeutically useful as result of an increased selectivity of action. In this study the tissue selectivity of three 8-alkylamino substituted analogues of N6-cyclopentyladenosine (CPA) was investigated for haemodynamic and anti-lipolytic effects using an integrated pharmacokinetic-pharmacodynamic approach. 2. Chronically instrumented male Wistar rats received intravenous infusions of 4.0 mg kg(-1) 8-methylaminoCPA (8MCPA), 12.0 mg kg(-1) 8-ethylaminoCPA (8ECPA), 20.0 mg kg(-1) 8-butylaminoCPA (8BCPA) or vehicle during 15 min. During experimentation, serial arterial blood samples were drawn for the determination of agonist concentrations and plasma non-esterified fatty acid (NEFA) levels. Blood pressure and heart rate were monitored continuously. In addition to the CPA analogues, each rat received a rapid bolus infusion of CPA to determine the maximal effects of the full agonist. 3. The concentration-time profiles of the CPA analogues could be described by a bi-exponential function. Values for clearance, volume of distribution at steady state and elimination half-life were 44+/-5, 48+/-6 and 39+/-2 ml min(-1) kg(-1), 0.97+/-0.09, 0.84+/-0.10 and 1.05+/-0.07 1 kg(-1) and 25+/-2, 28+/-2 and 40+/-2 min for 8MCPA, 8ECPA and 8BCPA, respectively (mean+/-s.e.mean, n=6-8). 4. Different models were used to derive the concentration-effect relationships for heart rate and NEFA, yielding estimates of potency (EC50) and intrinsic activity (Emax) for both effects of the compounds in vivo. On heart rate the compounds acted as partial agonists, with Emax values of -173+/-14, -131+/-11 and -71+/-6 beats min(-1) for 8MCPA, 8ECPA and 8BCPA, respectively. These Emax values were significantly lower than the maximal effect of CPA (-208+/-8 beats min(-1)). With regard to the anti-lipolytic effect all three compounds were full agonists and lowered NEFA levels to the same extent as CPA (69%). The estimated Emax values were 63+/-5, 63+/-4 and 68+/-2%, respectively. 5. Furthermore, the compounds were more potent in causing anti-lipolytic than cardiovascular effects. The EC50 values for the NEFA and heart rate lowering effects were 37+/-15, 68+/-22 and 659+/-108 ng ml(-1) and 164+/-22, 341+/-76 and 975+/-190 ng ml(-1) for 8MCPA, 8ECPA and 8BCPA, respectively (mean+/-s.e.mean, n=6-8). 6. This study demonstrates that partial agonists for the A1 adenosine receptor have increased selectivity of action in vivo. The 8-alkylamino analogues of CPA may be useful anti-lipolytics with less pronounced haemodynamic side effects.
