SELECTIVITY OF ACTION OF 8-ALKYLAMINO ANALOGS OF N-6-CYCLOPENTYLADENOSINE IN-VIVO - HEMODYNAMIC VERSUS ANTI-LIPOLYTIC RESPONSES IN RATS

1 A(1) adenosine receptor agonists with reduced intrinsic activity may be therapeutically useful as result of an increased selectivity of ac tion. In this study the tissue selectivity of three 8-alkylamino subst ituted analogues of N-6-cyclopentyladenosine (CPA) was investigated fo r haemodynamic and anti-lipolytic effects using an integrated pharmaco kinetic-pharmacodynamic approach. 2 Chronically instrumented male Wist ar rats received intravenous infusions of 4.0 mg kg(-1) 8-methylaminoC PA (8MCPA), 12.0 mg kg(-1) 8-ethylaminoCPA (8ECPA), 20.0 mg kg(-1) 8-b utylaminoCPA (8BCPA) or vehicle during 15 min. During experimentation, serial arterial blood samples were drawn for the determination of ago nist concentrations and plasma non-esterified fatty acid (NEFA) levels . Blood pressure and heart rate were monitored continuously. In additi on to the CPA analogues, each rat received a rapid bolus infusion of C PA to determine the maximal effects of the full agonist. 3 The concent ration-time profiles of the CPA analogues could be described by a bi-e xponential function. Values for clearance, volume of distribution at s teady 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 r ate and NEFA, yielding estimates of potency (EC50) and instrinsic acti vity (E-max) for both effects of the compounds in vivo. On heart rate the compounds acted as partial agonists, with E-max values of -173 +/- 14, -131 +/- 11 and -71 +/- 6 beats min(-1) for 8MCPA, 8ECPA and 8BCP A, respectively. These E-max values were significantly lower than the maximal effect of CPA (-208 +/- 8 beats min(-1)). With regard to the a ntilipolytic effect all three compounds were full agonists and lowered NEFA levels to the same extent as CPA (69%). The estimated E-max valu es were 63 +/- 5, 63 +/- 4 and 68 +/- 2%, respectively. 5 Furthermore, the compounds were more potent in causing anti-lipolytic than cardiov ascular 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 +/- 90 ng ml(-1) for 8MCPA, 8ECPA and 8BCPA, respectively (mean +/- s.e.mean, n = 6-8). 6 This study demonstrates t hat partial agonists for the A(1) adenosine receptor have increased se lectivity of action in vivo. The 8-alkylamino analogues of CPA may be useful anti-lipolytics with less pronounced haemodynamic side effects.