Document Detail

Comparative pharmacology of human adenosine receptor subtypes - characterization of stably transfected receptors in CHO cells.
MedLine Citation:
PMID:  9459566     Owner:  NLM     Status:  MEDLINE    
Four adenosine receptor subtypes of the family of G protein-coupled receptors, designated A1, A2A, A2B and A3 are currently known. In this study all human subtypes were stably transfected into Chinese hamster ovary (CHO) cells in order to be able to study their pharmacological profile in an identical cellular background utilizing radioligand binding studies (A1, A2A, A3) or adenylyl cyclase activity assays (A2B). The A1 subtype showed the typical pharmacological profile with 2-chloro-N6-cyclopentyladenosine (CCPA) as the agonist with the highest affinity and a marked stereoselectivity for the N6-phenylisopropyladenosine (PIA) diastereomers. In competition with antagonist radioligand biphasic curves were observed for agonists. In the presence of GTP all receptors were converted to a single low affinity state indicating functional coupling to endogenous G proteins. For A2A adenosine receptors CGS 21680 (2-[p-(2-carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoadeno sine) and N-ethylcarboxamidoadenosine (NECA) were found to be the most potent agonists followed by R- and S-PIA with minor stereoselectivity. The relative potencies of agonists for the A2B adenosine receptor could only be tested by measurement of receptor-stimulated adenylyl cyclase activity. NECA was the most potent agonist with an EC50-value of 2.3 microM whereas all other compounds tested were active at concentrations in the high micromolar range. Inhibition of NECA-stimulated adenylyl cyclase identified xanthine amino congener (XAC; 8-[4-[[[[(2-aminoethyl)amino]-carbonyl]methyl]oxy]phenyl]-1,3-dipropylxa nthine) as the most potent antagonist at this receptor subtype. The A3 receptor was characterized utilizing the nonselective agonist [3H]NECA. The N6-benzyl substituted derivatives of adenosine-5'-N-methyluronamide (MECA) turned out to be the most potent agonists. The notion of xanthine-insensitivity of the A3 receptor should be dropped at least for the human receptor as xanthines with submicromolar affinity were found. Overall, the pharmacological characteristics of the human receptors are similar to other species with some species-specific characteristics. In this study we present for the first time the comparative pharmacology of all known human adenosine receptor subtypes. The CHO cells with stably transfected adenosine receptors provide an identical cellular background for such a pharmacological characterization. These cells are valuable systems for further characterization of specific receptor subtypes and for the development of new ligands.
K N Klotz; J Hessling; J Hegler; C Owman; B Kull; B B Fredholm; M J Lohse
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Naunyn-Schmiedeberg's archives of pharmacology     Volume:  357     ISSN:  0028-1298     ISO Abbreviation:  Naunyn Schmiedebergs Arch. Pharmacol.     Publication Date:  1998 Jan 
Date Detail:
Created Date:  1998-03-11     Completed Date:  1998-03-11     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0326264     Medline TA:  Naunyn Schmiedebergs Arch Pharmacol     Country:  GERMANY    
Other Details:
Languages:  eng     Pagination:  1-9     Citation Subset:  IM    
Institut für Pharmakologie und Toxikologie, Universität Würzburg, Germany.
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MeSH Terms
Adenosine / analogs & derivatives,  pharmacology
Adenosine-5'-(N-ethylcarboxamide) / pharmacology
Base Composition
Binding, Competitive
CHO Cells / metabolism*
Guanylate Cyclase / metabolism
Phenethylamines / pharmacology
Phenylisopropyladenosine / metabolism
Receptors, Purinergic P1 / biosynthesis,  drug effects*,  genetics
Structure-Activity Relationship
Xanthines / pharmacology
Reg. No./Substance:
0/Phenethylamines; 0/Receptors, Purinergic P1; 0/Xanthines; 120225-54-9/CGS 21680; 29193-86-0/Phenylisopropyladenosine; 35788-27-3/5'-N-methylcarboxamideadenosine; 35920-39-9/Adenosine-5'-(N-ethylcarboxamide); 37739-05-2/2-chloro-N(6)cyclopentyladenosine; 58-61-7/Adenosine; 96865-92-8/8-(4-((2-aminoethyl)aminocarbonylmethyloxy)phenyl)-1,3-dipropylxanthine; EC Cyclase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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