title: Effects of the adenosine A1 receptor allosteric modulators PD 81,723 and LUF 5484 on the striatal acetylcholine release.
abstract: 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.
authors.affiliation: Research Group Medical Countermeasures, TNO Prins Maurits Laboratory, Lange Kleiweg 137, P.O. Box 45, 2280 AA Rijswijk, The Netherlands.
authors.forename: Tjerk J H
authors.initials: TJ
authors.lastname: Bueters
authors.forename: Herman P M
authors.initials: HP
authors.lastname: van Helden
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.forename: Ad P
authors.initials: AP
authors.lastname: IJzerman
mesh_terms: 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*
chemical_list: D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D013876:Thiophenes; C075004:PD 81723; D000109:Acetylcholine