Low efficacy adenosine A1 agonists inhibit striatal acetylcholine release in rats improving central selectivity of action.
The objective of this study was to characterize the effects of the adenosine A(1) receptor agonist N(6)-cyclopentyladenosine (CPA) and its low efficacy derivatives 2'-deoxy-CPA (2DCPA), 3'-deoxy-CPA (3DCPA), 8-ethylamino-CPA (8ECPA) and 8-butylamino-CPA (8BCPA) on the release of acetylcholine (ACh) using intrastriatal microdialysis. These low efficacy agonists exhibited lower effects on the cardiovascular system than CPA. A concentration-dependent inhibition of ACh release was observed with a maximum of 60.5+/-2.4% for CPA, 42.5+/-2.3% for 2DCPA, 45.3+/-5.8% for 3DCPA, 57.1+/-1.4% for 8ECPA and 93.1+/-10.9% for 8BCPA, respectively. This effect was counteracted by the adenosine A(1) receptor antagonist 8-cyclopentyltheophylline. These findings show that low efficacy adenosine A(1) agonists inhibit striatal ACh release equally effective as CPA, suggesting that central nervous system-selective actions can be obtained with these compounds.
Research Group Pharmacology, TNO Prins Maurits Laboratory, Lange Kleiweg 137, P.O. Box 45, 2280 AA Rijswijk, The Netherlands.
Tjerk J H
TJ
Bueters
Herman P M
HP
van Helden
Adriaan P
AP
IJzerman
Meindert
M
Danhof
D000109:Acetylcholine / Q000493:pharmacokinetics*; D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D008297:Male; D017551:Microdialysis / Q000379:methods; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism*; D058906:Purinergic P1 Receptor Agonists; D051381:Rats; D017208:Rats, Wistar; D043704:Receptor, Adenosine A2B; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
D058906:Purinergic P1 Receptor Agonists; D043704:Receptor, Adenosine A2B; C048599:N(6)-cyclopentyladenosine; D000241:Adenosine; D000109:Acetylcholine