Ea. Vanschaick et al., SELECTIVITY OF ACTION OF 8-ALKYLAMINO ANALOGS OF N-6-CYCLOPENTYLADENOSINE IN-VIVO - HEMODYNAMIC VERSUS ANTI-LIPOLYTIC RESPONSES IN RATS, British Journal of Pharmacology, 124(3), 1998, pp. 607-618
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.