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Low efficacy adenosine A1 agonists inhibit striatal acetylcholine release in rats improving central selectivity of action
| article |
2003
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| Author: |
Bueters, T.J.H.
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Helden, H.P.M. van
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IJzerman, A.P.
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Danhof, M.
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| Keywords: |
Acetylcholine · Adenosine · Adenosine A1 receptor · Low efficacy agonist · Microdialysis · Tissue selectivity · 2' deoxy 6 n cyclopentyladenosine · 3' deoxy 6 n cyclopentyladenosine · 6 n cyclopentyladenosine · 8 butylamino 6 n cyclopentyladenosine · 8 cyclopentyltheophylline · 8 ethylamino 6 n cyclopentyladenosine · Acetylcholine · Adenosine A1 receptor agonist · Unclassified drug · Acetylcholine release · Animal experiment · Animal tissue · Cardiovascular system · Controlled study · Corpus striatum · Dose response · Drug effect · Drug efficacy · Male · Microdialysis · Nonhuman · Rat · Animals · Dose-Response Relationship, Drug · Microdialysis · Neostriatum · Rats, Wistar · Receptor, Adenosine A2B · Receptors, Purinergic P1 · Reproducibility of Results · Sensitivity and Specificity · 6 n cyclopentyladenosine, 41552-82-3 · 8 cyclopentyltheophylline, 35873-49-5 · Acetylcholine, 51-84-3, 60-31-1, 66-23-9 · Adenosine, 58-61-7; · N(6)-cyclopentyladenosine, 41552-82-3 · Receptor, Adenosine A2B · Receptors, Purinergic P1
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The objective of this study was to characterize the effects of the adenosine A1 receptor agonist N6-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 A1 receptor antagonist 8-cyclopentyltheophylline. These findings show that low efficacy adenosine A1 agonists inhibit striatal ACh release equally effective as CPA, suggesting that central nervous system-selective actions can be obtained with these compounds. © 2003 Elsevier Science Ireland Ltd. All rights reserved.
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[Abstract]
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Cyclopentyladenosine and some of its low-efficacy derivatives inhibit striatal synaptosomal release of acetylcholine to a similar degree
| article |
2003
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| Author: |
Bueters, T.J.H.
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Duivenvoorde, L.M. van
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Danhof, M.
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IJzerman, A.P.
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Helden, H.P.M. van
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| Keywords: |
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
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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.
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[Abstract]
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