PMID- 10649980
OWN - NLM
STAT- MEDLINE
DCOM- 20000228
LR  - 20190709
IS  - 0022-2623 (Print)
IS  - 0022-2623 (Linking)
VI  - 43
IP  - 2
DP  - 2000 Jan 27
TI  - N-cycloalkyl derivatives of adenosine and 1-deazaadenosine as agonists and 
      partial agonists of the A(1) adenosine receptor.
PG  - 250-60
AB  - A number of cycloalkyl substituents (from C-3 to C-8) have been introduced on the 
      6-amino group of adenosine, 1-deazaadenosine, and 2'-deoxyadenosine, bearing or 
      not a chlorine atom at the 2-position, to evaluate the influence on the A(1) and 
      A(2A) affinity of steric hindrance and lipophilicity. Furthermore, the guanosine 
      5'-triphosphate (GTP) shift and the maximal induction of guanosine 
      5'-(gamma-thio)triphosphate ([(35)S]GTPgammaS) binding to G proteins in rat brain 
      membranes were used to determine the intrinsic activity of these nucleosides at 
      the A(1) adenosine receptor. All compounds of the ribose-bearing series proved to 
      be full agonists, the 1-deaza derivatives showing affinities for the A(1) 
      receptor about 10-fold lower than the corresponding adenosines. On the other 
      hand, all the 2'-deoxyribose derivatives bind to the A(1) receptor with 
      affinities in the high nanomolar range, with the 2-chloro substituted compounds 
      showing slightly higher affinities than the 2-unsubstituted counterparts. In 
      terms of the potencies, the most potent compounds proved to be those bearing 
      four- and five-membered rings. Both GTP shifts and [(35)S]-GTPgammaS experiments 
      showed that most of the 2'-deoxyadenosine derivatives are partial agonists. The 
      2'-deoxyadenosine derivatives which were identified as partial agonists 
      consistently detected fewer A(1) receptors in the high-affinity state than full 
      agonists. However, it is worthwhile noting that there was not a simple linear 
      relationship between receptor occupancy and activation. These results indicate 
      that a critical density of A(1) adenosine receptors in the high-affinity state is 
      required for G protein activation.
FAU - Vittori, S
AU  - Vittori S
AD  - Dipartimento di Scienze Chimiche, Universita di Camerino, 62032 Camerino, Italy.
FAU - Lorenzen, A
AU  - Lorenzen A
FAU - Stannek, C
AU  - Stannek C
FAU - Costanzi, S
AU  - Costanzi S
FAU - Volpini, R
AU  - Volpini R
FAU - IJzerman, A P
AU  - IJzerman AP
FAU - Kunzel, J K
AU  - Kunzel JK
FAU - Cristalli, G
AU  - Cristalli G
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Phenethylamines)
RN  - 0 (Purinergic P1 Receptor Agonists)
RN  - 0 (Xanthines)
RN  - 120225-54-9 (2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine)
RN  - 14432-09-8 (1-deazaadenosine)
RN  - 37589-80-3 (Guanosine 5'-O-(3-Thiotriphosphate))
RN  - 9PTP4FOI9E (1,3-dipropyl-8-cyclopentylxanthine)
RN  - K72T3FS567 (Adenosine)
RN  - M351LCX45Y (Tubercidin)
SB  - IM
MH  - Adenosine/analogs & derivatives/chemistry/metabolism/*pharmacology
MH  - Animals
MH  - Brain/drug effects/metabolism
MH  - Guanosine 5'-O-(3-Thiotriphosphate)/metabolism
MH  - Magnetic Resonance Spectroscopy
MH  - Phenethylamines/metabolism
MH  - *Purinergic P1 Receptor Agonists
MH  - Radioligand Assay
MH  - Rats
MH  - Tubercidin/chemistry/*pharmacology
MH  - Xanthines/metabolism
EDAT- 2000/01/29 09:00
MHDA- 2000/03/04 09:00
CRDT- 2000/01/29 09:00
PHST- 2000/01/29 09:00 [pubmed]
PHST- 2000/03/04 09:00 [medline]
PHST- 2000/01/29 09:00 [entrez]
AID - jm9911231 [pii]
AID - 10.1021/jm9911231 [doi]
PST - ppublish
SO  - J Med Chem. 2000 Jan 27;43(2):250-60. doi: 10.1021/jm9911231.