title: Cyclopentyladenosine and some of its low-efficacy derivatives inhibit striatal synaptosomal release of acetylcholine to a similar degree.
abstract: The application of adenosine A(1) receptor agonists in regard to cerebral disorders is hampered by serious cardiovascular side effects. This problem might be circumvented by using low-efficacy agonists (partial agonists). The objective of the present study was to characterize the effects of the full agonist N(6)-cyclopentyladenosine (CPA) and its low-efficacy derivatives 3'-deoxy-CPA (3-DCPA), 8-propylamino-CPA (8-PCPA) and 8-butylamino-CPA (8-BCPA) on the 4-aminopyridine (4AP)-evoked release of [3H]-acetylcholine in a rat striatal synaptosomal system. The reason for studying these partial agonists in particular was their established low cardiovascular side effect profile. CPA reached a concentration-dependent maximal inhibition of the evoked acetylcholine release of 38+/-3%. 3-DCPA and 8-PCPA inhibited the acetylcholine release by 29+/-5% and 38+/-3%, respectively. On the other hand, 8-BCPA only diminished the acetylcholine release by 19+/-3%. This inhibitory effect was reversible upon coadministration of the nonselective adenosine antagonist theophylline, but not by the selective adenosine A(2A) receptor antagonist 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (SCH 58261). It is concluded that some partial adenosine A(1) receptor agonists behave as full agonists with respect to the inhibition of acetylcholine release, while lacking profound cardiovascular side effects. These preliminary results encourage further investigation of their tissue selectivity and therapeutic potential in vivo.
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: Leonie M
authors.initials: LM
authors.lastname: van Duivenvoorde
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.forename: Ad P
authors.initials: AP
authors.lastname: IJzerman
authors.forename: Herman P M
authors.initials: HP
authors.lastname: van Helden
mesh_terms: D000109:Acetylcholine / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism
chemical_list: C048599:N(6)-cyclopentyladenosine; D000241:Adenosine; D000109:Acetylcholine