Title
Cyclopentyladenosine and some of its low-efficacy derivatives inhibit striatal synaptosomal release of acetylcholine to a similar degree
Author
Bueters, T.J.H.
van Duivenvoorde, L.M.
Danhof, M.
IJzerman, A.P.
van Helden, H.P.M.
Prins Maurits Laboratorium TNO TNO Preventie en Gezondheid
Publication year
2003
Abstract
The application of adenosine A1 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 N6-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 A2A 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. © 2003 Elsevier B.V. All rights reserved.
Subject
Biology
3D-CPA (3′-deoxy-CPA)
8-BCPA (8-butylamino-CPA)
8-PCPA (8-propylamino-CPA)
Acetylcholine release
Adenosine A1 receptor
CPA (cyclopentyladenosine)
Low-efficacy agonist
Neuronal synaptosome
Partial agonist
3' deoxy 6 n cyclopentyladenosine
8 butylamino 6 n cyclopentyladenosine
8 propylamino 6 n cyclopentyladenosine
Adenosine A2 receptor antagonist
Adenosine derivative
Adenosine receptor blocking agent
Partial agonist
Tritium
Unclassified drug
Animal tissue
Brain synaptosome
Cardiotoxicity
Concentration response
Controlled study
Corpus striatum
Drug effect
Evoked response
Inhibition kinetics
Male
Nonhuman
Rat
Adenosine
Animals
Dose-Response Relationship, Drug
Rats, Wistar
Synaptosomes
4 aminopyridine, 1003-40-3, 504-24-5
5 amino 2 (2 furyl) 7 (2 phenylethyl)pyrazolo[4,3 e][1,2,4]triazolo[1,5 c]pyrimidine, 160098-96-4
6 n cyclopentyladenosine, 41552-82-3
Acetylcholine, 51-84-3, 60-31-1, 66-23-9
Theophylline, 58-55-9, 5967-84-0, 8055-07-0, 8061-56-1, 99007-19-9
Tritium, 10028-17-8
Adenosine, 58-61-7
N(6)-cyclopentyladenosine, 41552-82-3
To reference this document use:
http://resolver.tudelft.nl/uuid:116821d9-ecac-499f-986c-8be8faaa1dc7
DOI
https://doi.org/10.1016/j.ejphar.2003.09.027
TNO identifier
237415
ISSN
0014-2999
Source
European Journal of Pharmacology, 481 (2-3), 141-146
Document type
article