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1.  The role of adenosine receptors in the central action of caffeine 
Pharmacopsychoecologia  1994;7(2):201-213.
The behavioral effects of caffeine appear likely to be due in large measure to antagonism of the action of endogenous adenosine at A1- and A2a-receptors in the central nervous system. Other biochemical mechanisms of action of caffeine, such as release of intracellular calcium, inhibition of phosphodiesterases and blockade of regulatory sites of GABAA-reccptors, would require much higher concentrations than the micromolar concentrations of caffeine associated with behavioral stimulation. However, micromolar concentrations of caffeine also would be expected to cause only a modest blockade of adenosine receptors. Selective adenosine agonists and xanthine antagonists have provided some insights into central roles for adenosine receptor subtypes. Thus, behavioral stimulation by xanthines appears to require blockade of both A1- and A2a-receptors. Chronic blockade of adenosine receptors by caffeine would be expected to result in alterations in the central receptors and pathways that are regulated by adenosine through A1- and A2a-receptors. Indeed, chronic caffeine docs alter the density not only of adenosine receptors, but also of adrenergic, cholinergic, GABAergic and serotonergic receptors. Behavioral responses to agents acting through dopaminergic and cholinergic pathways arc altered. As yet, a coherent explanation of the acute and chronic effects of caffeine in terms of blockade of adenosine receptors has not emerged. Interactions between pathways subserved by A1 - and A2a-adcnosine receptors complicate attempts to interpret caffeine pharmacology, as does the complex control by adenosine receptors of dopamincrgic, cholinergic and other central pathways.
PMCID: PMC4373791  PMID: 25821357
Adenosine receptors; Calcium storage; Phosphodiesterase; Dopamine; Cocaine; Amphetamine; Nicotine; Muscarinic antagonists
Life sciences  1986;38(9):797-807.
Six amine, amino acid and peptide derivatives derived from 1,3-dipropyl-8-(p-carboxymethylphenyl)xanthine, a functionalized congener of 1,3-dipropyl-8-phenylxanthine, have been investigated as antagonists at A2A adenosine receptors stimulatory to adenylate cyclase in membranes from rat pheochrornocytoma PC 12 cells and human platelets and at A1 adenosine receptors inhibitory to adenylate cyclase from rat fat cells. The functionalized congeners and conjugates have affinity constants ranging from 80 to 310 nM at A2A receptors of PC 12 cells and from 25 to 135 nM at those of platelets. The affinity of the xanthine derivatives at A1 receptors of fat cells are in the 15 to 30 nM range. Thus, the amino acid and peptide conjugates have high potencies at both receptor subclasses and show some selectivity toward A1 adenosine receptors. Derivatives of the congeners should be useful as receptor probes and as radioiodinated ligands.
PMCID: PMC4364026  PMID: 3005794
Adenosine analogues substituted at N6 with spacer arms designed for attachment to soluble macromolecules or to solid supports for affinity chromatography are agonists at the A2–adenosine receptor that mediates coronary vasodilation in the dog. The most active analogues had spacer arms terminating in −NH2, −NHCH3 or in a biotin residue. Comparisons of coronary vasoactivity with affinity" for brain A1 adenosine receptors identified one biotin–containing analogue as relatively selective for coronary A2 receptors. The complex of this analogue with avidin retained coronary vasoactivity.
PMCID: PMC4364609  PMID: 3013167
4.  A [3H]amine congener of 1,3-dipropyl-8-phenylxanthine 
FEBS letters  1986;199(2):269-274.
A xanthine amine congener (XAC), an amine-functionalized derivative of 1,3-dipropyl-8-phenylxanthine, is an antagonist ligand for A2 adenosine receptors of human platelets. XAC inhibited 5′-N-ethylcarboxamidoadenosine (NECA)-induced stimulation of adenylate cyclase activity with a KB of 24 nM. [3H]XAC exhibits saturable, specific binding with a Kd of 12 nM and a Bmax of 1.1 pmol/mg protein at 37°C. [3H]XAC binding in platelets is the first example of labeling of A2 adenosine receptors in which the potencies of adenosine agonists and antagonists in inhibiting binding are commensurate with their potencies at these receptors in functional studies. Furthermore, [3H]XAC is the first antagonist radioligand with high affinity at A2 adenosine receptors.
PMCID: PMC4351550  PMID: 3009222
Adenosine receptor; Platelet; Xanthine
5.  A role for central A3-adenosine receptors Mediation of behavioral depressant effects 
FEBS letters  1993;336(1):57-60.
The behavioral effects of a selective A3 adenosine receptor agonist 3-IB-MECA (N6-(3-iodobenzyl)-5′-N-methylcarboxamidoadenosine) in mice and the localization of radioligand binding sites in mouse brain were examined. Low levels of A3 adenosine receptors were detected in various regions of the mouse brain (hippocampus, cortex, cerebellum, striatum), using a radioiodinated, high-affinity Aragonist radioligand [125I]AB-MECA (N6-(3-iodo-4-aminobenzyl)-5′-N-methylcarboxamidoadenosine). Scatchard analysis in the cerebellum showed that the Kd value for binding to A3 receptors was 1.39 ± 0.04 nM with a Bmax of 14.8 ± 2.1 fmol/mg protein. 3-IB-MECA at 0.1 mg/kg i.p. was a locomotor depressant with> 50% reduction in activity. Although selective A1 or A2a antagonists reversed locomotor depression elicited by selective A1 or A2a agonists, respectively, the behavioral depressant effects of 3-IB-MECA were unaffected. 3-IB-MECA also caused scratching in mice, which was prevented by coadministration of the histamine antagonist cyproheptadine. The demonstration of a marked behavioral effect of A3 receptor activation suggests that the A3 receptor represents a potential new therapeutic target.
PMCID: PMC4287251  PMID: 8262217
Adenosine receptor; Xanthine; Locomotor activity; Histamine; Radioligand binding
6.  Adenosine analogs with covalently attached lipids have enhanced potency at A1-adenosine receptors 
FEBS letters  1987;225(0):97-102.
Chemically functionalized congeners of N6-phenyladenosine and I ,3-dipropyl-8-phenylxanthine have been covalently coupled to fatty acids, diglyceridcs, and a phospholipid. The lipid-drug conjugates inhibit R-[3H]-phenylisopropyladenosinc binding to A1-adcnosine receptors in rat cerebral cortex membranes. A xanthinepbosphatidylethanolaminc conjugate bound with a K1 value of 19 nM. Various xanthine esters of low potency are potential prod rugs. Amides of an adenosine amine congener (ADA C) with 18-carbon fatty acids exhibited Ki values at A1-adenosine receptors of 70 pM, representing a 130-fold enhancement over the affinity of the corresponding acetyl amide. The very high affinity of adenosine-lipid conjugates may be due to stabilization of these adducts in the phospholipid microenvironment of the receptor protein.
PMCID: PMC4287258  PMID: 3691809
Lipid; Adenosine receptor; Xanthine; Adenosine derivative; Lipid-drug conjugate; Prodrug
7.  Locomotor Activity in Mice During Chronic Treatment With Caffeine and Withdrawal 
Chronic ingestion of caffeine by mice caused a marked reduction in locomotor exploratory activity. At least 4 days of withdrawal were required to restore activity to normal levels. Stimulatory effects of injected caffeine were lower in chronically treated mice and the biphasic dose-response (stimulatory followed by depressant) curve for injected caffeine was left shifted. Seven days of withdrawal were required before the dose-response curve to caffeine was identical to that of control mice. The depressant effects of a potent xanthine phosphodiesterase inhibitor, 1,3-dipropyl-7-methylxanthine, were blunted in caffeine-treated mice. The depressant effects of A1- and A2-selective adenosine analogs were enhanced after chronic caffeine. There was little or no effect of chronic caffeine on the stimulatory effects of dopaminergic agents (amphetamine, caffeine), while both depressant and stimulatory effects of chollnergic agents (nicotine, oxotremorine, scopolamine) were reduced. The results indicate that chronic caffeine affects functions of adenosine and chollnergic receptors related to regulation of locomotor exploratory activity.
PMCID: PMC3557839  PMID: 7679219
Caffeine; Adenosine receptors; Cocaine; Amphetamine; Chollnergic receptors; Nicotine; Locomotor activity
8.  Activation and Desensitization of Rat A3-Adenosine Receptors by Selective Adenosine Derivatives and Xanthine-7-Ribosides 
Drug development research  1998;44(2-3):97-105.
Strategy, Management and Health PolicyVenture Capital Enabling TechnologyPreclinical ResearchPreclinical Development Toxicology, Formulation Drug Delivery, PharmacokineticsClinical Development Phases I-III Regulatory, Quality, ManufacturingPostmarketing Phase IV
Xanthine and adenosine derivatives, known to bind to recombinant rat A3 adenosine receptors stably expressed in Chinese hamster ovary cells, were characterized in a functional assay consisting of activation of A3 receptor-stimulated binding of [35S]GTPγS in rat RBL-2H3 cell membranes. 1,3-Dibutylxanthine-7-riboside-5′-N-methylcarboxamide (DBXRM, 7b), previously shown to inhibit adenylyl cyclase via rat A3 receptors with full efficacy, appeared to be a partial agonist at the rat A3 receptor of RBL-2H3 cells. Full agonists, such as Cl-IB-MECA or I-AB-MECA, were more potent and effective than the partial agonist DBXRM in causing desensitization of rat A3 receptors, as indicated by loss of [35S]GTPγS binding. At A1 receptors, antagonism of agonist-elicited inhibition of rat adipocyte adenylyl cyclase was observed for several xanthine-7-riboside derivatives that had been shown to be full agonists at rat A3 receptors. A new xanthine riboside (3′-deoxyDBXRM, 7c) was synthesized and found to be a partial agonist at rat A3 receptors and an antagonist at rat A1 receptors. Thus, it is possible for the same compound to stimulate one adenosine receptor subtype (A3) and block another subtype (A1) within the same species.
PMCID: PMC3589805  PMID: 23487508
xanthines; adenosine derivatives; nucleosides; adenylyl cyclase; guanine nucleotides
9.  Sulfur-Containing 1,3-Dialkylxanthine Derivatives as Selective Antagonists at A1-Adenosine Receptors 
Journal of medicinal chemistry  1989;32(8):1873-1879.
Sulfur-containing analogues of 8-substituted xanthines were prepared in an effort to increase selectivity or potency as antagonists at adenosine receptors. Either cyclopentyl or various aryl substituents were utilized at the 8-position, because of the association of these groups with high potency at A1-adenosine receptors. Sulfur was incorporated on the purine ring at positions 2 and/or 6, in the 8-position substituent in the form of 2- or 3-thienyl groups, or via thienyl groups separated from an 8-aryl substituent through an amide-containing chain. The feasibility of using the thienyl group as a prosthetic group for selective iodination via its Hg2+ derivative was explored. Receptor selectivity was determined in binding assays using membrane homogenates from rat cortex [[3H]-N6-(phenylisopropyl) adenosine as radioligand] or striatum [[3H]-5′-(N-ethylcarbamoyl)adenosine as radioligand] for A1- and A2-adenosine receptors, respectively. Generally, 2-thio-8-cycloalkylxanthines were at least as A1 selective as the corresponding oxygen analogue. 2-Thio-8-aryl derivatives tended to be more potent at A2 receptors than the oxygen analogue. 8-[4-[(Carboxymethyl)oxy]phenyl]-1,3-dipropyl-2-thioxanthine ethyl ester was >740-fold A1 selective.
PMCID: PMC3479653  PMID: 2754711
Life sciences  1989;45(8):719-728.
The convulsant properties of xanthine amine congener (XAC, 8-(4-(2-aminoethyl)-aminocarboxylmethyloxy)phenyl-1,3-dipropylxanthine) are compared to those of caffeine. Male Swiss albino mice were infused with convulsants through a lateral tail vein. Convulsion thresholds (i.e. the amount of convulsants required to elicit convulsions) of 39.8±2.0 mg/kg (n=10) and 109.8±2.3 mg/kg (n=10) were calculated for XAC and caffeine respectively. Pretreatment of animals with the adenosine receptor agonists 2-chloroadenosine, N6-cyclohexyladenosine or 5′-N-ethylcarboxamido-adenosine (1 mg/kg, i.p., 20 minutes prior to infusion) significantly decreased the seizure threshold of both XAC and caffeine. The adenosine uptake blockers, 6-nitrobenzylthioinosine or dipyridamole (0.25 mg/kg, i.p., 20 minutes prior to infusion) did not significantly affect the seizure threshold to either XAC or caffeine. The benzodiazepine agonist diazepam (5 mg/kg, i.p., 20 minutes prior to infusion) significantly increased the seizure threshold to both XAC (p < 0.05) and caffeine (p < 0.01), whereas the benzodiazepine antagonist Ro 15-1788 (10 mg/kg, i.p., 20 minutes prior to infusion) significantly increased the seizure threshold to caffeine (p < 0.01), but not XAC. The results suggest that actions at benzodiazepine receptors may be a tenable hypothesis to explain the convulsant actions of caffeine, but not those of XAC.
PMCID: PMC3478950  PMID: 2779359
11.  Activation of Phosphoinositide Breakdown and Elevation of Intracellular Calcium in a Rat RBL-2H3 Mast Cell Line by Adenosine Analogs: Involvement of A3-Adenosine Receptors? 
Drug development research  1996;39(1):36-46.
A variety of adenosine analogs activate phosphoinositide breakdown in a rat RBL-2H3 mast cell line. It is presumed that an A3-adenosine receptor is involved, since the phosphoinositide response is insensitive to xanthines. However, the very potent A3- receptor agonist 2-chloro-N6-iodobenzyl-N-methylcarboxamidoadenosine (2-CI-IBMECA) with an EC50 of 4.1 µM is about twofold less potent (and less efficacious) than N-ethylcarboxamidoadenosine (NECA) with an EC50 of 2.1 µM. The other agents consisting of N6-p-aminophenylethyladenosine (APNEA), N6-iodobenzylMECA (IB-MECA), N6-R- phenylisopropyladenosine (R-PIA), 2-chloroadenosine, N6-benzyladenosine, N6- cyclohexyladenosine (CHA), N6-cyclohexylNECA (CHNECA), 2-(p- carboxyethylphenyl-ethylaminoNECA (CGS 21680), 1,3-dibutylxanthine 7-riboside-5′-N-methylcarboxamide (DBXRM), adenosine, and 8-bromoadenosine are all nearly equipotent with EC50 values of 5.5-13.9 µM. The rank order of potencies of the analogs in causing an elevation of intracellular calcium is quite different. The potent A3 receptor agonists 2-CI-IBMECA and IB-MECA with EC50 values of 0.07 and 0.11 µM, respectively, are about fourfold more potent than N6-cyclohexylNECA and about 15-fold more potent than NECA. The other analogs are comparable or somewhat less potent than NECA, some are less efficacious, and 8-bromoadenosine is inactive. The results suggest that stimulation of phosphoinositide breakdown by adenosine analogs in RBL-2H3 cells as measured by IP1 accumulation is not predictive of IP3-mediated elevations of intracellular calcium. Rank order of potency for the calcium response is consonant with intermediacy of A3-adenosine receptors, while the former, as measured by [3H]IP1-formation, probably reflects contributions from both an A3-mediated response and some other mechanism. Combinations of subthreshold concentrations of 2-CI-IBMECA with either the A1-selective agonist CHA or the A2A-selective agonist CGS 21680 caused a marked stimulation of phosphoinositide breakdown, providing further evidence for dual mechanisms. The selective A3-adenosine receptor antagonist 3,6-dichloro-2′-(isopropyloxy)-4′-methylflavone (MRS 1067) inhibits 2-CI-IBMECA- and NECA-elicited elevation of calcium levels, and had differential effects on phosphoinositide breakdown, blocking [3H]IP3 accumulation and either blocking (NECA) or having no effect (2-CI-IBMECA) on [3H]IP1 accumulation.
PMCID: PMC3475513  PMID: 23087534
adenosine receptors; phosphoinositides; calcium; xanthines
12.  Characterization of the locomotor depression produced by an A2-selective adenosine agonist 
FEBS letters  1990;261(1):67-70.
Adenosine analogs, such as N6-cyclohexyladenosine (CHA) that are selective for A1-adenosine receptors, and analogs, such as 5′-N-ethylcarboxamidoadenosine (NECA) that are active at both A1 and A2 receptors, cause a profound depression of locomotor activity in mice via a central mechanism. The depression is effectively reversed by non-selective adenosine antagonists such as theophylline. We report that 2-[(2-aminoethyl-amino)carbonylethylphenylethylamino]-5′-N-ethylcarboxamidoadenosine (APEC), an amine derivative of the A2-selective agonist, CGS21680, is a potent locomotor depressant in mice. The in vivo pharmacology is consistent with A2-selectivity at a central site of action. Two parameters indicative of locomotor activity, horizontal activity and total distance travelled, were measured using a computerized activity monitor. From dose-response curves it was found that APEC (ED50 16 μg/kg) is more potent than CHA (ED50 60 μg/kg) and less potent than NECA (ED50 2 μg/kg). The locomotor depression by APEC was reversible by theophylline, but not by the A1-selective antagonists 8-cyclopentyltheophylline (CPT) and 8-cyclopentyl-1,3-dipropyl-2-thioxanthine, nor by the peripheral antagonists 8-p-sulfophenyltheophylline (8-PST) and 1,3-dipropyl-8-p-sulfophenylxanthine. The locomotor activity depression elicited by NECA and CHA was reversed by A1-selective antagonists. These results suggest that the effects of APEC are due to stimulation of A2 adenosine receptors in the brain.
PMCID: PMC3469261  PMID: 2307237
Adenosine analog; Locomotor depression; Adenosine receptor
13.  Species differences in structure-activity relationships of adenosine agonists and xanthine antagonists at brain A1 adenosine receptors 
FEBS letters  1986;209(1):122-128.
A series of 28 adenosine analogs and 17 xanthines has been assessed as inhibitors of binding of N6-R-[3H]-phenylisopropyladenosine binding to A1 adenosine receptors in membranes from rat, calf, and guinea pig brain. Potencies of N6-alkyl- and N6-cycloalkyladenosines are similar in the different species. However, the presence of an aryl or heteroaryl moiety in the N6 substituent results in marked species differences with certain such analogs being about 30-fold more potent at receptors in calf than in guinea pig brain. Potencies at receptors in rat brain are intermediate. Conversely, 2-chloroadenosine and 5′-N-ethylcarboxamido-adenosine are about 10-fold less potent at receptors in calf brain than in guinea pig brain. Potencies of xanthines, such as theophylline, caffeine and 1,3-dipropylxanthine are similar in the different species. However, the presence of an 8-phenyl or 8-cycloalkyl substituent results in marked species differences. For example, a xanthine amine conjugate of 1,3-dipropyl-8-phenylxanthine is 9-fold more potent at receptors in calf than in rat brain and 110-fold more potent in calf than in guinea pig brain. Such differences indicate that brain A1 adenosine receptors are not identical in recognition sites for either agonists or antagonists in different mammalian species.
PMCID: PMC3469266  PMID: 3803571
Adenosine agonist; Xanthine antagonist; Adenosine receptor; Structure-activity
14.  Functionalized Congeners of Adenosine: Preparation of Analogues with High Affinity for A1-Adenosine Receptors 
Journal of medicinal chemistry  1985;28(9):1341-1346.
A series of functionalized congeners of adenosine based on N6-phenyladenosine, a potent A1-adenosine receptor agonist, was synthesized. Derivatives of the various congeners should be useful as receptor and histochemical probes and for the preparation of radioligands and affinity columns or as targeted drugs. N6-[4-(Carboxymethyl)phenyl]adenosine served as the starting point for synthesis of the methyl ester, the methyl amide, the ethyl glycinate, and various substituted anilides. One of the latter, N6-[4-[[[4-(carbomethoxymethyl)anilino]carbonyl]methyl]phenyl]adenosine, served as the starting point for the synthesis of another series of congeners including the methyl amide, the hydrazide, and the aminoethyl amide. The terminal amino function of the last congener was acylated to provide further analogues. The various congeners were potent competitive antagonists of binding of N6-[3H]cyclohexyladenosine to A1-adenosine receptors in rat cerebral cortical membranes. The affinity of the congener for the A1 receptor was highly dependent on the nature of the spacer group and the terminal moiety with Ki values ranging 1–100 nM. A biotinylated analogue had a Ki value of 11 nM. A conjugate derived from the Bolton–Hunter reagent had a Ki value of 4.5 nM. The most potent congener contained a terminal [(aminoethyl)amino]carbonyl function and had a Ki value of less than 1 nM.
PMCID: PMC3469267  PMID: 2993623
Biochemical pharmacology  1988;37(19):3653-3661.
Two classes of 8-substituted analogs of theophylline (1,3-dialkylxanthines), having 8-cycloalkyl, 8-cycloalkenyl or 8-(para-substituted aryl) groups, were shown to be potent and, in some cases, receptor subtype selective antagonists at A1- and A2-adenosine receptors. New analogs based on a functionalized cogener approach and on classical medicinal chemical approaches were prepared. Affinity at A1-adenosine receptors was evaluated by inhibition of binding of [3H)N6-phenylisopropyladenosine to rat brain membranes. Activity at A2A-adenosine receptors was measured by the reversal of 5′-N-ethylcarboxamidoadenosine (NECA)-stimulated production of cyclic AMP in membranes from rat pheochromocytoma PC12 cells. Cycloalkenyl analogs containing rigid olefinic bonds differed greatly in potency from the saturated analogs. The selectivity of phenylsulfonamide analogs depended on distal structural features. Novel xanthine analogs include diamino-, thiol-, aldehyde, and halogen-substituted derivatives, peptide conjugates of 8-[4-[2-aminoethylaminocarbonylmethyloxy]phenyl]1,3-dipropylxanthine (XAC), and a hydroxyethylamide analog of XAC.
PMCID: PMC3469272  PMID: 3178879
16.  Functionalized Congeners of 1,3-Dialkylxanthines: Preparation of Analogues with High Affinity for Adenosine Receptors 
Journal of medicinal chemistry  1985;28(9):1334-1340.
A series of functionalized congeners of 1,3-dialkylxanthines has been prepared as adenosine receptor antagonists. On the basis of the high potency of 8-(p-hydroxyphenyl)-1,3-dialkylxanthines, the parent compounds were 8-[4-[(carboxymethyl)oxy]phenyl] derivatives of theophylline and 1,3-dipropylxanthine. A series of analogues including esters of ethanol and N-hydroxysuccinimide, amides, a hydrazide, an acylurea, and anilides were prepared. The potency in blocking A1-adenosine receptors (inhibition of binding of N6-[3H]cyclohexyladenosine to brain membranes) and A2-adenosine receptors (inhibition of 2-chloroadenosine-elicited accumulations of cyclic AMP in brain slices) was markedly affected by structural changes distal to the primary pharmacophore (8-phenyl-1,3-dialkylxanthine). Potencies in the dipropyl series at the A1 receptor ranged from K1 values of 1.2 nM for a congener with a terminal amidoethyleneamine moiety to a K1 value of 58 nM for the parent carboxylic acid to a K1 of 96 nM for the bulky ureido congener. Certain congeners were up to 145-fold more active at A1 receptors than at A2 receptors. Various derivatives of the congeners should be useful as receptor probes and for radioidodination, avidin binding, and preparation of affinity columns.
PMCID: PMC3468300  PMID: 2993622
17.  8-(3-Chlorostyryl)caffeine (CSC) is a selective A2-adenosine antagonist in vitro and in vivo 
FEBS letters  1993;323(1-2):141-144.
An adenosine antagonist, 8-(3-chlorostyryl)caffeine (CSC), was shown previously to be 520-fold selective for A2a-adenosine receptors in radioligand binding assays in the rat brain. In reversing agonist effects on adenylate cyclase, CSC was 22-fold selective for A2d receptors in rat pheochromocy-toma cells (Kb 60 nM) vs. A1 receptors in rat adipocytes (Kb 1.3 µM). Administered i.p. in NIH mice at a dose of 1 mg/kg, CSC shifted the curve for locomotor depression elicited by the A2a-selective agonist APEC to the right (ED50, value for APEC shifted from 20 µg/kg i.p. to 190 µg/kg). CSC had no effect on locomotor depression elicited by an ED50 dose of the A1-selective agonist CHA. CSC alone at a dose of 5 mg/kg stimulated locomotor activity by 22% over control values. Coadministration of CSC and the A1-selective antagonist CPX, both at non-stimulatory doses, increased activity by 37% (P < 0.001) over CSC alone, suggesting a behavioral synergism of A1- and A2-antagonist effects in the CNS.
PMCID: PMC3468328  PMID: 8495727
Adenosine receptor; Xanthine; Locomotor activity; Dopamine; Adenylate cyclase
18.  A Functionalized Congener Approach to Adenosine Receptor Antagonists: Amino Acid Conjugates of 1,3-Dipropylxanthine 
Molecular pharmacology  1986;29(2):126-133.
1,3-Dipropyl-8-phenylxanthine, a synthetic analog of theophylline and a potent antagonist of adenosine at A1 and A2-adenosine receptors, has been attached covalently through a functionalized chain to amino acids and oligopeptides. The xanthine conjugates have been studied as competitive inhibitors of the specific binding of [3H]N6-cyclohexyladenosine to A1-receptors of rat cerebral cortical membranes and for inhibition of cyclic AMP accumulation elicited by 2-chloroadenosine in guinea pig brain slices through A2-receptors. A free amino group on the extended chain generally resulted in high potency at A1-receptors. The potency (in some cases extending into the subnanomolar range) and selectivity for A1-receptors (up to 200-fold) suggest that this approach can yield a versatile class of “functionalized congeners” of adenosine receptor antagonists in which distal modifications of the attached moiety (“carrier”) can serve also to improve pharmacodynamic and pharmacokinetic parameters. The water solubility in many of the more potent analogs has been enhanced by two orders of magnitude over that of simple, uncharged 8-phenyl xanthine derivatives. Analogs in which the carrier contains d-tyrosine have potential for development of iodinated radioligands for adenosine receptors. The functionalized congener approach is potentially applicable to other drugs and for development of prodrugs.
PMCID: PMC3459325  PMID: 3005825
19.  Probing the adenosine receptor with adenosine and xanthine biotin conjugates 
FEBS letters  1985;184(1):30-35.
Biotin-containing analogs of a potent agonist (N6-phenyladenosine) and a potent antagonist (1,3-dipropyl-8-phenylxanthine) of adenosine receptor activity have been synthesized. A spacer chain to the biotin moiety is attached in both cases to the para-position of the phenylring. Two biotin conjugates of N6-phenyladenosine differing only in the length of the spacer chain bind to the adenosine receptor and to avidin simultaneously. The shorter-chain derivative was more potent in inhibiting binding of N6-[3H]cyclohexyladenosine to rat cerebral cortical membranes (K1 of 11 nM in the absence of avidin, 36 nM for the avidin complex). Three biotin conjugates of 1,3-dipropyl-8-phenylxanthine bound competitively to the adenosine receptor, but only in the absence of avidin. The results are interpreted in terms of the possible orientation of the ligands at the receptor binding site.
PMCID: PMC3445621  PMID: 2985445
Adenosine receptor; Biotin; Avidin; Functionalized congener; N6-Phenyladenosine; Xanthine
Biochemical pharmacology  1988;37(4):655-664.
A variety of non-xanthine heterocycles were found to be antagonists of binding of [3H]phenylisopropyladenosine to rat brain A1-adenosine receptors and of activation of adenylate cyclase via interaction of N-ethylcarboxarnidoadenosine with A2-adenosine receptors in human platelet and rat pheochromocytoma cell membranes. The pyrazolopyridines tracazolate, cartazolate and etazolate were several fold more potent than theophylline at both A1- and A2-adenosine receptors. The pyrazolopyridines, however, were still many fold less potent than 8-phenyltheophylline and other 8-phenyl-1,3-dialkylxanthines. A structurally related N6-substituted 9-methyladenine was also a potent adenosine antagonist with selectivity for A1 receptors. None of several aryl-substituted heterocycles, including a thiazolopyrimidine, imidazopyridines, benzimidazoles, a pyrazoloquinoline, a mesoionic xanthine analog and a triazolopyridazine exhibited the high potency typical of 8-phenyl-1,3-dialkylxanthines. A furyl-substituted triazoloquinazoline was very potent at both A1 and A2 receptors. A pteridin-2,4-dione, 1,3-dipropyllumazine, was somewhat less potent than theophylline at A1- and A2-adenosine receptors, whereas 1,3-dimethyllumazine was much less potent. A benzopteridin-2,4-dione, alloxazine, was somewhat more potent than theophylline. Other heterocycles with antagonist activity were the dibenzazepine carbamazepine and β-carboline-3-ethyl carboxylate. The phenylimidazoline clonidine had no activity, whereas a related dihydroxyphenylimidazoline was a weak non-competitive adenosine antagonist.
PMCID: PMC3445624  PMID: 2829919
21.  Chronic Caffeine Alters the Density of Adenosine, Adrenergic, Cholinergic, GABA, and Serotonin Receptors and Calcium Channels in Mouse Brain 
1. Chronic ingestion of caffeine by male NIH strain mice alters the density of a variety of central receptors.
2. The density of cortical A1 adenosine receptors is increased by 20%, while the density of striatal A2A adenosine receptors is unaltered.
3. The densities of cortical β1 and cerebellar β2 adrenergic receptors are reduced by ca. 25%, while the densities of cortical α1 and α2 adrenergic receptors are not significantly altered. Densities of striatal D1 and D2 dopaminergic receptors are unaltered. The densities of cortical 5 HT1 and 5 HT2 serotonergic receptors are increased by 26–30%. Densities of cortical muscarinic and nicotinic receptors are increased by 40–50%. The density of cortical benzodiazepine-binding sites associated with GABAA receptors is increased by 65%, and the affinity appears slightly decreased. The density of cortical MK-801 sites associated with NMDA-glutaminergic receptors appear unaltered.
4. The density of cortical nitrendipine-binding sites associated with calcium channels is increased by 18%.
5. The results indicate that chronic ingestion of caffeine equivalent to about 100 mg/kg/day in mice causes a wide range of biochemical alterations in the central nervous system.
PMCID: PMC3437321  PMID: 8242688
caffeine; adenosine receptors; adrenergic receptors; cholinergic receptors; serotonin receptors; GABA receptors; calcium channels; dopamine receptors; NMDA receptors
22.  Xanthine Functionalized Congeners as Potent Ligands at A2-Adenosine Receptors†,‡ 
Journal of medicinal chemistry  1987;30(1):211-214.
Amide derivatives of a carboxylic acid congener of 1,3-dialkylxanthine, having a 4-[(carboxymethyl)oxy]phenyl substituent at the 8-position, have been synthesized in order to identify potent antagonists at A2-adenosine receptors stimulatory to adenylate cyclase in platelets. Distal structural features of amide-linked chains and the size of the 1,3-dialkyl groups have been varied. 1,3-Diethyl groups, more than 1,3-dimethyl or 1,3-dipropyl groups, favor A2 potency, even in the presence of extended chains attached at the 8-(p-substituted-phenyl) position. Polar groups, such as amines, on the chain simultaneously enhance water solubility and A2 potency. Among the most potent A2 ligands are an amine congener, 8-[4-[[[[(2-aminoethyl)amino]carbonyl]methyl]oxy]phenyl]-1,3-diethylxanthine, and its D-lysyl conjugate, which have KB values of 21 and 23 nM, respectively, for the antagonism of N-ethyl-adenosine-5′-uronamide-stimulated adenylate cyclase activity in human platelet membranes. Strategies for the selection and tritiation of new radioligands for use in competitive binding assays at A2-adenosine receptors have been considered.
PMCID: PMC3433718  PMID: 3806597
23.  Adenosine receptor ligands: differences with acute versus chronic treatment 
Adenosine receptors have been the target of intense research with respect to potential use of selective ligands in a variety of therapeutic areas. Caffeine and theophylline are adenosine receptor antagonists, and over the past three decades a wide range of selective agonists and antagonists for adenosine receptor subtypes have been developed. A complication to the therapeutic use of adenosine receptor ligands is the observation that the effects of acute administration of a particular ligand can be diametrically opposite to the chronic effects of the same ligand. This ‘effect inversion’ is discussed here by Ken Jecobson and colleagues, and has been observed for effects on cognitive processes, seizures and ischaemic damage.
PMCID: PMC3431161  PMID: 8936347
24.  Chronic NMDA receptor stimulation: therapeutic implications of its effect on adenosine A1 receptors 
European journal of pharmacology  1995;283(1-3):185-192.
It is known that stimulation of adenosine A1 receptors has a modulatory effect on the excitability of postsynaptic NMDA receptors. Conversely, acute stimulation of NMDA receptors results in release of adenosine via calcium-independent mechanisms. These findings indicate a close functional relationship between these receptors. It is, therefore, possible that chronic, low level stimulation of the NMDA receptor may have a negative impact on these modulatory processes. To investigate this possibility, we have subjected C57BL mice either to an acute injection of a N6-cyclopentyladenosine (CPA, 0.01 mg/kg) or deoxycoformycin (1 mg/kg) followed by a convulsant dose of N-methyl-d-aspartate (NMDA) (60 mg/kg) or to chronic, low level (20 mg/kg i.p. daily) exposure to NMDA for 8 weeks. One day after the last injection of NMDA, animals were injected either with a convulsant dose of NMDA alone, or with either CPA at 0.001 or 0.01 mg/kg, or with 1 mg/kg deoxycoformycin followed 15 min later by 60 mg/kg NMDA. Neither CPA nor deoxycoformycin were protective when NMDA was given acutely at 60 mg/kg. Chronic treatment with NMDA alone or chronic administration of NMDA followed by 0.001 mg/kg CPA had no significant effect on mortality following a convulsant dose of NMDA. However, when the chronic regimen of NMDA was followed by either 0.01 mg/kg CPA or 1 mg/kg deoxycoformycin, mortality was reduced to 10% (CPA), or eliminated completely (deoxycoformycin). Moreover, combination of chronic NMDA treatment with either CPA (both doses) or deoxycoformycin produced a significant improvement in other measures, i.e., seizure onset, intensity of neurological impairment, and extension of time to death. Consonant with these results, apparent density of adenosine A1 receptors was increased in the cortex and hippocampus of animals treated chronically with NMDA. Our results indicate a possible role for NMDA-adenosine A1 receptor interaction in pathologies in which chronic stimulation of the NMDA receptor by endogenous excitatory amino acids may be involved.
PMCID: PMC3427754  PMID: 7498308
Adenosine A1 receptor; NMDA receptor; Seizure; Alzheimer’s disease; (Mouse)
25.  Behavioral Effects of A1- and A2-Selective Adenosine Agonists and Antagonists: Evidence for Synergism and Antagonism 
The locomotor effects in mice of selective A1 and A2 adenosine agonists, antagonists and combinations of agonists were investigated using a computerized activity monitor. The A2-selective agonist 2-[(2-aminoethylamino)carbonylethylphenylethylamino]-5'-N-ethylcarboxamidoadenosine (APEC), an amine derivative of 2-(carboxyethylphenylethylamino)adenosine-5'-carboxamide, was a more potent locomotor depressant than its amide conjugates. The rank order of potency after i.p. injection for adenosine agonists was 5'-N-ethylcarboxamidoadenosine (NECA) (ED50, 5.8 nmol/kg) > APEC (ED50, 25 nmol/kg) > N6-cyclohexyladenosine (CHA) (ED50, 270 nmol/kg). An A1-selective, centrally acting, adenosine antagonist, 8-cyclopentyltheophylline (10 mg/kg), completely reversed the locomotor depressant effects of CHA (A1-selective) and NECA (nonselective) at doses of agonists as high as twice the ED50, and shifted the dose-response curves to the right, suggesting a primary involvement of A1 receptors. 8-cyclopentyltheophylline did not affect the depressant effects of APEC at the ED50, consistent with the A2-selectivity of APEC. The locomotor effects of APEC and CHA were completely reversed by theophylline, but not by the peripherally active 8-p-sulfophenyltheophylline, indicating central action of the adenosine agonists. The depressant effects of APEC, but not of NECA or CHA, were reversed significantly by an A2-selective adenosine receptor antagonist, 4-amino-8-chloro-1-phenyl-[1,2,4]triazol[4,3-a]quinoxaline. Low or subthreshold doses of CHA potentiated the depressant effects of APEC. A subthreshold dose of CHA did not alter the depressant effect of NECA, whereas a subthreshold dose of APEC increased the depressant effects of low doses of NECA. Thus, it appears that A1- and A2-selective adenosine agonists have separate central depressant effects, which can be potentiative. The relatively high potency of NECA in vivo could be due to a synergism between central A1 and A2receptor activation by this nonselective agonist.
PMCID: PMC3425643  PMID: 1920121

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