Author: von Frijtag Drabbe Kunzel, Jacobien K. ; van den Hoven, Thijs ; van der Klein, Pieter A. M. ; van Westhoven, Rosemarijn ; Brussee, Johannes ; Ait El Maate, Fatna ; Fujikawa, Shelly ; IJzerman, Ad P. ; Lorenzen, Anna ; de Ligt, Rianne A. F.

Novel 3,8- and 8,9-disubstituted N(6)-cyclopentyladenine derivatives were synthesised in moderate overall yield from 6-chloropurine. The derivatives were made in an attempt to find a new neutral antagonist with high affinity for adenosine A(1) receptors. N(6)-Cyclopentyl-9-methyladenine (N-0840) was used as a lead compound. Binding affinities of the new analogues were determined for human adenosine A(1) and A(3) receptors. Their intrinsic activity was assessed in [35S]GTPgammaS binding experiments. Elongation of the 9-methyl of N-0840 to a 9-propyl substituent was very well tolerated. A 9-benzyl group, on the other hand, caused a decrease in adenosine A(1) receptor affinity. Next, the 8-position was examined in detail, and affinity was increased with appropriate substitution. Most derivatives were A(1)-selective and 20 of the new compounds (6-9, 15-21, 23-26, 28, 31, 33, 35, and 36) had higher adenosine A(1) receptor affinity than the reference substance, N-0840. Compound 31 (N(6)-cyclopentyl-8-(N-methylisopropylamino)-9-methyladenine, LUF 5608) had the highest adenosine A(1) receptor affinity, 7.7 nM. In the [35S]GTPgammaS binding experiments, derivatives 5, 14, 22, 23, 25, 26, 33 and 34 did not significantly change basal [35S]GTPgammaS binding, thus behaving as neutral antagonists. Moreover, four of these compounds (23, 25, 26, and 33) displayed a 4- to 10-fold increased adenosine A(1) receptor affinity (75-206 nM) compared to N-0840 (852 nM). In summary, we synthesised a range of N-0840 analogues with higher affinity for adenosine A(1) receptors. In addition, four new derivatives, LUF 5666 (23), LUF 5668 (25), LUF 5669 (26) and LUF 5674 (33), behaved as neutral antagonists when tested in [35S]GTPgammaS binding studies. Thus, these compounds have improved characteristics as neutral adenosine A(1) receptor antagonists.

01 Oct 1999·The Journal of pharmacology and experimental therapeutics

Role of adenosine A(1) receptors in modulating extracellular adenosine levels.

Article

Author: Gillespie, D G ; Jackson, E K ; Andresen, B T ; Mi, Z ; Dubey, R K

The purpose of this investigation was to test the hypothesis that A(1) receptors modulate extracellular levels of adenosine in cardiovascular tissues. Rat cardiac fibroblasts and human aortic vascular smooth muscle cells were cultured to confluence and various pharmacological agents were applied to the cultures. The extracellular fluid was extracted and adenosine concentrations were measured by HPLC. Three selective A(1) receptor antagonists, namely 8-cyclopentyl-1,3-dipropylxanthine, xanthine amine congener, and N-0840, at a concentration of 10 nM significantly increased extracellular levels of adenosine in both rat cardiac fibroblasts and human aortic vascular smooth muscle cells. Further studies in rat cardiac fibroblasts revealed that the effects of A(1) receptor blockade on extracellular adenosine levels were concentration dependent and prevented by inhibition of G(i) proteins with pertussis toxin or blockade of ecto-5'-nucleotidase with alpha, beta-methyleneadenosine-5'-diphosphate. In cardiac fibroblasts in which the extracellular levels of endogenous adenosine were increased, the ability of A(1) receptor blockade to augment extracellular adenosine was attenuated. A time-course study revealed a time lag of several hours between blockade of A(1) receptors and increases in extracellular adenosine levels. These data suggest that A(1) receptors function to detect the long-term levels of extracellular adenosine, and appropriately adjust extracellular adenosine levels by a slow-onset mechanism involving G(i) proteins and ecto-5'nucleotidase.

01 May 1998·Molecular pharmacology

Inverse agonists and neutral antagonists of recombinant human A1 adenosine receptors stably expressed in Chinese hamster ovary cells.

Article

Author: Ozeck, M J ; Shryock, J C ; Belardinelli, L

Receptor antagonists can be classified as neutral antagonists or antagonists with inverse agonist activity based on their effectiveness to reduce the spontaneous agonist-independent activity of receptors. The goals of this study were to (1) demonstrate that A1-adenosine receptors (A1AdoRs) expressed at high density (4000-8000 fmol/mg of protein) in Chinese hamster ovary (CHO) cells cause constitutive activation of inhibitory G proteins and inhibition of adenylyl cyclase activity and (2) identify both neutral A1AdoR antagonists and antagonists with inverse agonist activity. The activity of A1AdoR agonists and antagonists was determined by assays of both specific binding of [35S]guanosine-5'-O-(3-thio)triphosphate ([35S]GTPgammaS) to membranes and cAMP content of intact cells in the presence of adenosine deaminase (2-5 units/ml). The A1AdoR agonist N6-cyclopentyladenosine (CPA) significantly increased binding of [35S]GTPgammaS by 241 +/- 7% compared with control. The A1AdoR antagonists N-0861, N-0840, and WRC-0342 did not alter binding of [35S]GTPgammaS, whereas the antagonists 8-cyclopentyl-1, 3-dipropylxanthine (CPX), CGS-15943, xanthine amine congener, and WRC-0571 significantly reduced binding of [35S]GTPgammaS by 28-53% from control, respectively. The effects of both the agonist N6-cyclopentyladenosine (CPA) and the antagonist CPX to alter binding of [35S]GTPgammaS were attenuated by 1 micro M N-0861. CPA reduced cAMP content of forskolin-stimulated CHO:A1AdoR cells, and N-0861 and WRC-0342 did not alter cAMP content, but the antagonists CPX and WRC-0571 increased the cAMP content of CHO:A1AdoR cells. The effects of both CPX and WRC-0571 to increase cAMP content of forskolin-stimulated CHO:A1AdoR cells were attenuated by either N-0861 or WRC-0342. The results indicate that both N-0861 and WRC-0342 are neutral antagonists, whereas both CPX and WRC-0571 are antagonists with inverse agonist activity.

100 Deals associated with N-0840

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Indication	Highest Phase	Country/Location	Organization	Date
Angina Pectoris	Discovery	BE	UCB SA	-
Peripheral Vascular Diseases	Discovery	BE	UCB SA	-

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