Photoisomerization of a potent and selective adenosine A2 antagonist, (E)-1,3-dipropyl-8-(3,4-dimethoxystyryl)-7-methylxanthine

Nonaka, Yoshiko; Shimada, Junichi; Nonaka, Hiromi; Koike, Nobuaki; Aoki, Noboru; Kobayashi, Hiroyuki; Kase, Hiroshi; Yamaguchi, Kazuo; Suzuki, Fumio

doi:10.1021/jm00075a031

Cited by 72 publications

(48 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These authors used 1 U/ml ADA, which we have shown to be insufficient to reveal the second high-affinity binding site for E3H]CGS 21680, and performed their study at low pH. Since the pH aValues for A1 receptors are from Bruns et al (1987), Jacobson et al (1985), Jacobson et al (1986), Jacobson et al (1993b), Nonaka et al (1993), , Bruns ct al. (1986), Hutchison et al (1989), Jacobson et al (1989) (2) greater sensitivity to Gpp(NH)p and sodium; (3) higher Kd for CGS 21680; and (4) densities in the cortex and hippocampus greater than those reported with other A2A ligands (Nokada et al 1994).…”

Section: Discussionmentioning

confidence: 99%

Evidence for high-affinity binding sites for the adenosine A2A receptor agonist [3H] CGS 21680 in the rat hippocampus and cerebral cortex that are different from striatal A2A receptors

Johansson

Constantino

et al. 1996

Naunyn-Schmiedeberg's Arch Pharmacol

176

120

View full text Add to dashboard Cite

The binding of the adenosine A2A receptor selective agonist 2-[4-(2-p-carboxyethyl)phenylamino] -5'-N-ethylcarboxamidoadenosine (CGS 21680) to the rat hippocampal and cerebral cortical membranes was studied and compared with that to striatal membranes. [3H] CGS 21680, in the concentration range tested (0.2-200 nM), bound to a single site with a Kd of 58 nM and a Bmax of 353 fmol/mg protein in the hippocampus, and with a Kd of 58 nM and a Bmax of 264 fmol/mg protein in the cortex; in the striatum, the single high-affinity [3H] CGS 21680 binding site had a Kd of 17 nM and a Bmax of 419 fmol/mg protein. Both guanylylimidodiphosphate (100 microM) and Na+ (100 mM) reduced the affinity of [3H] CGS 21680 binding in the striatum by half and virtually abolished [3H] CGS 21680 binding in the hippocampus and cortex. The displacement curves of [3H] CGS 21680 binding with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), N6-cyclohexyladenosine (CHA), 5'-N-ethylcarboxamidoadenosine (NECA) and 2-chloroadenosine (CADO) were biphasic in the hippocampus and cortex as well as in the striatum. The predominant [3H]CGS 21680 binding site in the striatum (80%) had a pharmacological profile compatible with A2A receptors and was also present in the hippocampus and cortex, representing 10-25% of [3H]CGS 21680 binding. The predominant [3H]CGS 21680 binding site in the hippocampus and cortex had a pharmacological profile distinct from A2A receptors: the relative potency order of adenosine antagonists DPCPX, 1,3-dipropyl- 8-¿4-[(2-aminoethyl)amino]carbonylmethyl- oxyphenyl¿ xanthine (XAC), 8-(3-chlorostyryl)caffeine (CSC), and (E)-1,3-dipropyl-8-(3,4-dimethoxystyryl)- methylxanthine (KF 17,837) as displacers of [3H] CGS 21680 (5 nM) binding in the hippocampus and cerebral cortex was DPCPX > XAC >> CSC approximately KF 17,837, and the relative potency order of adenosine agonists CHA, NECA, CADO, 2-[(2-aminoethylamino)carbonylethylphenylethylamino]-5'-N- ethylcarboxamidoadenosine (APEC), and 2-phenylaminoadenosine (CV 1808) was CHA approximately NECA > or = CADO > APEC approximately CV1808 > CGS 21680. In the presence of DPCPX (20 nM), [3H] CGS 21680 (0.2-200 nM) bound to a site (A2A-like) with a Kd of 20 nM and a Bmax of 56fmol/mg protein in the hippocampus and with a Kd of 22 nM and a Bmax of 63fmol/mg protein in the cortex. In the presence of CSC (200 nM), [3H]CGS 21680(0.2-200 nM) bound to a second high-affinity site with a Kd of 97 nM and a Bmax of 255 fmol/mg protein in the hippocampus and with a Kd of 112 nM and a Bmax of 221 fmol/mg protein in the cortex. Two pharmacologically distinct [3H]CGS 21680 binding sites were found in synaptosomal membranes of the hippocampus and cortex and in the striatum, one corresponding to A2A receptors and the other to the second high-affinity [3H]CGS 21680 binding site. In contrast, the pharmacology of [3H]CHA binding was similar in synaptosomal membranes of the three brain areas. The present results establish the existence of at least two high-affinity [3H]CGS 21680 binding sites in the CNS and demonstrate t...

show abstract

Section: Discussionmentioning

confidence: 99%

Evidence for high-affinity binding sites for the adenosine A2A receptor agonist [3H] CGS 21680 in the rat hippocampus and cerebral cortex that are different from striatal A2A receptors

Johansson

Constantino

et al. 1996

Naunyn-Schmiedeberg's Arch Pharmacol

176

120

View full text Add to dashboard Cite

show abstract

“…[115] However, several problems such as the poor water solubility [116] and the fact that these compounds rapidly photoisomerize when exposed to normal daylight in dilute solution, have initially limited the use of these compounds as pharmacological tools (Figure 4). [117] This process is not present when styrylxanthines are applied perorally as solid substances, but during binding studies, performed in buffer solution and in the presence of light, the phenomenon occurs very rapidly. For instance, (E) KF17837 (36) becomes, after photoisomerization, a stable mixture of~18 % (E) (36) and~82 % (Z) (38) of the two isomers, giving in a binding study the following data: K i A 2A = 7.9 nm, K i A 1 = 390 nm.…”

Section: Xanthine Derivativesmentioning

confidence: 99%

“…For instance, (E) KF17837 (36) becomes, after photoisomerization, a stable mixture of~18 % (E) (36) and~82 % (Z) (38) of the two isomers, giving in a binding study the following data: K i A 2A = 7.9 nm, K i A 1 = 390 nm. [117] Moreover, several styryl xanthines have been synthesized and different ratios of (E)/(Z) mixtures have been observed, but usually the (Z) isomer is predominant. [118] On this class of compounds a great SAR profile has been generated, through modification of all the positions of the xan-268 www.chemmedchem.org thine nucleus.…”

Section: Xanthine Derivativesmentioning

confidence: 99%

Highlights on the Development of A_2A Adenosine Receptor Agonists and Antagonists

et al. 2007

View full text Add to dashboard Cite

Although significant progress has been made in the past few decades demonstrating that adenosine modulates a variety of physiological and pathophysiological processes through the interaction with four subtypes of a family of cell-surface G-protein-coupled receptors, clinical evaluation of some adenosine receptor ligands has been discontinued. Major problems include side effects due to the wide distribution of adenosine receptors, low brain penetration (which is important for the targeting of CNS diseases), short half-life of compounds, or a lack of effects, in some cases perhaps due to receptor desensitization or to low receptor density in the targeted tissue. Currently, three A(2A) adenosine receptor agonists have begun phase III studies. Two of them are therapeutically evaluated as pharmacologic stress agents and the third proved to be effective in the treatment of acute spinal cord injury (SCI), while avoiding the adverse effects of steroid agents. On the other hand, the great interest in the field of A(2A) adenosine receptor antagonists is related to their application in neurodegenerative disorders, in particular, Parkinson's disease, and some of them are currently in various stages of evaluation. This review presents an update of medicinal chemistry and molecular recognition of A(2A) adenosine receptor agonists and antagonists, and stresses the strong need for more selective ligands at the A(2A) human subtype.

show abstract

“…After completion of these studies, Nonaka et al (1993) (Jacobson et al, 1993b). Additional studies are therefore necessary to define better the profile of the A2 antagonist xanthines before their use as reference tools in experimental studies.…”

Section: *0mentioning

confidence: 99%

Effects of the new A₂ adenosine receptor antagonist 8FB‐PTP, an 8 substituted pyrazolo‐triazolo‐pyrimidine, on in vitro functional models

Dionisotti¹,

Conti²,

Sandoli³

et al. 1994

British J Pharmacology

View full text Add to dashboard Cite

1 We have characterized the in vitro pharmacological profile of putative A2 adenosine antagonists, two non-xanthine compounds, 5-amino-8-(4-fluorobenzyl)-2-(2-furyl)-pyrazolo [4,3-e]-1,2,4-triazolo[l ,5-c] pyrimidine (8FB-PTP) and 5-amino-9-chloro-2-(2-furyl 1,2,4-triazolo [1,5-c] quinazoline (CGS 15943), and the xanthine derivative (E)7-methyl-8-(3,4-dimethoxystyryl)-1,3-dipropyl-xanthine (KF 17837).2 In binding studies on bovine brain, 8FB-PTP was the most potent (Ki = 0.074 nM) and selective (28 fold) drug on A2 receptors, whereas CGS 15943 and KF 17837 exhibited affinity in the low and high nanomolar range, respectively, and showed little selectivity. The data provided a basis to reduce, by further chemical modifications, the affinity at Al receptor and therefore enhance A2 receptor selectivity.

show abstract

Photoisomerization of a potent and selective adenosine A2 antagonist, (E)-1,3-dipropyl-8-(3,4-dimethoxystyryl)-7-methylxanthine

Cited by 72 publications

References 4 publications

Evidence for high-affinity binding sites for the adenosine A2A receptor agonist [3H] CGS 21680 in the rat hippocampus and cerebral cortex that are different from striatal A2A receptors

Evidence for high-affinity binding sites for the adenosine A2A receptor agonist [3H] CGS 21680 in the rat hippocampus and cerebral cortex that are different from striatal A2A receptors

Highlights on the Development of A_2A Adenosine Receptor Agonists and Antagonists

Effects of the new A₂ adenosine receptor antagonist 8FB‐PTP, an 8 substituted pyrazolo‐triazolo‐pyrimidine, on in vitro functional models

Contact Info

Product

Resources

About

Photoisomerization of a potent and selective adenosine A2 antagonist, (E)-1,3-dipropyl-8-(3,4-dimethoxystyryl)-7-methylxanthine

Cited by 72 publications

References 4 publications

Evidence for high-affinity binding sites for the adenosine A2A receptor agonist [3H] CGS 21680 in the rat hippocampus and cerebral cortex that are different from striatal A2A receptors

Evidence for high-affinity binding sites for the adenosine A2A receptor agonist [3H] CGS 21680 in the rat hippocampus and cerebral cortex that are different from striatal A2A receptors

Highlights on the Development of A2A Adenosine Receptor Agonists and Antagonists

Effects of the new A2 adenosine receptor antagonist 8FB‐PTP, an 8 substituted pyrazolo‐triazolo‐pyrimidine, on in vitro functional models

Contact Info

Product

Resources

About

Highlights on the Development of A_2A Adenosine Receptor Agonists and Antagonists

Effects of the new A₂ adenosine receptor antagonist 8FB‐PTP, an 8 substituted pyrazolo‐triazolo‐pyrimidine, on in vitro functional models