Effects of the adenosine A1 receptor allosteric modulators PD 81,723 and LUF 5484 on the striatal acetylcholine release.
The objective of the present study was to characterize the adenosine A(1) receptor allosteric enhancing and antagonistic actions of (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(3,4-dichlorophenyl)methanone (LUF 5484) and (2-amino-4,5-dimethyl-3-thienyl)-[3-(trifluoromethyl)phenyl]methanone (PD 81,723) on striatal acetylcholine release. Upon local administration in conscious rats, LUF 5484 or PD 81,723 caused a concentration-dependent increase of extracellular acetylcholine levels of approximately 40%, which was similar to that obtained by the selective adenosine A(1) receptor antagonists 8-cyclopentyl-1,3-dimethylxanthine (8CPT) and N(6)-cyclopentyl-9-methyladenine (N0840). In interaction experiments, LUF 5484 or PD 81,723 did not change the inhibition of acetylcholine release by the adenosine A(1) receptor agonist N(6)-cyclopentyladenosine (CPA), whereas 8CPT caused an eightfold rightward shift. Acetylcholine concentrations were diminished with 62+/-3%, 48+/-11% and 56+/-9% by CPA, CPA+LUF 5484 and CPA+PD 81,723, respectively. In conclusion, the antagonistic action of LUF 5484 and PD 81,723 seems to counteract the putative allosteric actions with respect to the reduction of striatal acetylcholine release.
Bueters
Tjerk J H
TJ
Research Group Medical Countermeasures, TNO Prins Maurits Laboratory, Lange Kleiweg 137, P.O. Box 45, 2280 AA Rijswijk, The Netherlands.
van Helden
Herman P M
HP
Danhof
Meindert
M
IJzerman
Ad P
AP
D000109:Acetylcholine / Q000378:metabolism*; D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008297:Male; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology*
D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D013876:Thiophenes; C075004:PD 81723; D000109:Acetylcholine