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Biomedical subjects

K A Jacobson

Publications and source records attributed to K A Jacobson.

At least 217 records · Page 12Linked to original sources
PubMed1988

Non-xanthine heterocycles: activity as antagonists of A1- and A2-adenosine receptors.

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-ethylcarboxamidoadenosine with A2-adenosine receptors in human platelet and rat phenochromocytoma 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 beta-carboline-3-ethyl carboxylate. The phenylimidazoline clonidine had no activity, whereas a related dihydroxyphenylimidazoline was a weak non-competitive adenosine antagonist.

Adenosine↗
PubMed1988

Multiple components of the A1 adenosine receptor-adenylate cyclase system are regulated in rat cerebral cortex by chronic caffeine ingestion.

The effects of chronic caffeine on the A1 adenosine receptor-adenylate cyclase system of rat cerebral cortical membranes were studied. Caffeine treatment significantly increased the number of A1 adenosine receptors as determined with the A1 adenosine receptor antagonist radioligand [3H]xanthine amine congener (XAC). R-PIA (agonist) competition curves constructed with [3H]XAC were most appropriately described by a two affinity state model in control membranes with a KH of 2.1 +/- 0.8 and a KL of 404 +/- 330 nM with 50 +/- 4% of receptors in the high affinity state (%RH). In contrast, in membranes from treated animals, there was a marked shift towards the high affinity state. In three of seven animals all of the receptors were shifted to a unique high affinity state which was indistinguishable from the KH observed in membranes from control animals. In four of seven animals the %RH increased from 50 to 69% with KH and KL indistinguishable from the control values. Thus, the agonist specific high affinity form of the receptor was enhanced following caffeine treatment. Maximal inhibition of adenylate cyclase activity in cerebral cortical membranes by R-PIA (1 microM) was significantly increased by 28% following caffeine treatment, consistent with an increased coupling of receptor-Gi protein with adenylate cyclase. Importantly, the quantity of Gi (alpha i) in rat cerebral cortex, determined by pertussis toxin-mediated labeling, was also increased to 133% of control values by this treatment. Thus, multiple components and interactions of the A1 adenosine receptor-adenylate cyclase complex are regulated by caffeine. These changes are likely compensatory measures to offset blockade of A1 receptors in vivo by caffeine and lead to a sensitization of this inhibitory receptor system.

Adenylyl Cyclase Inhibitors↗
PubMed1988

High affinity acylating antagonists for the A1 adenosine receptor: identification of binding subunit.

Two isomeric isothiocyanate derivatives of the A1 adenosine receptor antagonist xanthine amine cogener (XAC) have been synthesized and found to be potent affinity labels (irreversibly bound ligands) for A1 adenosine receptors. The interaction of m- and p-isomers of 1,3-dipropyl-8-isothiocyanatophenyl(aminothiocarbonyl (2-aminoethylaminocarbonyl(4-methyloxy(phenyl]])-xanthine (DITC-XAC) with rat brain A1 receptors is of high affinity (EC50 = 27 and 52 nM, respectively) as determined by radioligand competition curves. These compounds reduced the number of A1 receptors (greater than 90% at 500 nM m-DITC-XAC) in brain membranes, without any change in the affinity of the remaining receptors for [125I]N6-2-(4-aminophenyl)ethyladenosine. Prior reaction of the isothiocyanate moiety with ethylenediamine did not alter the affinity of the XAC derivative for the A1 receptor but eliminated its ability to covalently incorporate into the receptor. Incubation of brain membranes with radiolabeled p- and m-DITC-XAC results in the specific labeling of a Mr 38,000 peptide. This labeling can be blocked with both an A1 adenosine receptor-specific agonist and an antagonist. This specific protein has the same molecular weight as the protein labeled with A1-selective photoaffinity probes. The much higher efficiency of incorporation of these affinity probes compared with photoaffinity probes should make them extremely useful for structural studies of A1 adenosine receptors.

Affinity Labels↗
PubMed1987

Adenosine analogs with covalently attached lipids have enhanced potency at A1-adenosine receptors.

Chemically functionalized congeners of N6-phenyladenosine and 1,3-dipropyl-8-phenylxanthine have been covalently coupled to fatty acids, diglycerides, and a phospholipid. The lipid-drug conjugates inhibit R-[3H]-phenylisopropyladenosine binding to A1-adenosine receptors in rat cerebral cortex membranes. A xanthine-phosphatidylethanolamine conjugate bound with a Ki value of 19 nM. Various xanthine esters of low potency are potential prodrugs. Amides of an adenosine amine congener (ADAC) 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.

Adenosine↗
PubMed1987

Autoradiographic localization of adenosine A1 receptors in rat brain using [3H]XCC, a functionalized congener of 1,3-dipropylxanthine.

Quantitative autoradiography was used to visualize the anatomical distribution of adenosine receptors labeled by the carboxylic acid congener of 1,3-dipropylxanthine, [3H](8-(p-carboxymethyloxy)phenyl-1,3-dipropylxanthine)([3H]XCC ) in the rat brain. [3H]XCC was observed to specifically bind to rat brain sagittal sections in a heterogeneous pattern. Saturation experiments revealed that [3H]XCC binds with nanomolar affinity to 20-microns frozen tissue sections with the highest binding densities occurring in the hippocampus and cerebellum. Both the binding characteristics and regional receptor distribution obtained with [3H]XCC demonstrate the potential usefulness of this new ligand in the study of adenosine A1 receptors.

Animals↗
PubMed1987

Molecular probes for extracellular adenosine receptors.

Derivatives of adenosine receptor agonists (N6-phenyladenosines) and antagonists (1,3-dialkyl-8-phenylxanthines) bearing functionalized chains suitable for attachment to other molecules have been reported [Jacobson et al., J. med. Chem. 28, 1334 and 1341 (1985)]. The "functionalized congener" approach has been extended to the synthesis of spectroscopic and other probes for adenosine receptors that retain high affinity (Ki approximately 10(-9)-10(-8) M) in A1-receptor binding. The probes have been synthesized from an antagonist xanthine amine congener (XAC) and an adenosine amine congener (ADAC). [3H]ADAC has been synthesized and found to bind highly specifically to A1-adenosine receptors of rat and calf cerebral cortical membranes with KD values of 1.4 and 0.34 nM respectively. The higher affinity in the bovine brain, seen also with many of the probes derived from ADAC and XAC, is associated with phenyl substituents. The spectroscopic probes contain a reporter group attached at a distal site of the functionalized chain. These bifunctional ligands may contain a spin label (e.g. the nitroxyl radical TEMPO) for electron spin resonance spectroscopy, or a fluorescent dye, including fluorescein and 4-nitrobenz-2-oxa-1,3-diazole (NBD), or labels for 19F nuclear magnetic resonance spectroscopy. Potential applications of the spectroscopic probes in characterization of adenosine receptors are discussed.

Affinity Labels↗
PubMed1987

Liquid chromatographic assay for cerebrospinal fluid normetanephrine.

A method for quantitation of normetanephrine in human cerebrospinal fluid is described. An amine-specific reagent, sulfosuccinimidyl propionate, is used to obtain the lipid soluble N-propionyl derivative of normetanephrine, which can be separated and quantitated in presence of other biogenic amines by liquid chromatography with electrochemical detection. The method is reproducible, linear, and precise at the relatively low concentrations of unconjugated normetanephrine occurring in human cerebrospinal fluid. Hospitalized, drug-free, alcoholic patients were found to have cerebrospinal fluid unconjugated normetanephrine concentrations in the 0.5-1.5 nanomolar range. The practical limit of sensitivity for the method is about 0.025 pmole per ml of CSF.

Acylation↗
PubMed1987

Xanthine functionalized congeners as potent ligands at A2-adenosine receptors.

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.

Adenylyl Cyclases↗
PubMed1987

Binary drugs: conjugates of purines and a peptide that bind to both adenosine and substance P receptors.

A "functionalized congener" approach to adenosine receptor antagonists has provided a means to synthesize highly potent peptide conjugates of 1,3-dialkylxanthines. The antagonist XAC, such a functionalized xanthine amine congener, has been attached to a segment derived from the neurotransmitter peptide substance P (SP) to form a binary drug that binds to both receptors with Ki values of 35 nM (central A1-adenosine) and 300 nM (striatal SP). Coupling of the functionalized adenosine agonist N6-[p-(carboxymethyl)phenyl]adenosine to an SP C-terminal peptide also resulted in a binary drug that binds to both receptors. The demonstration that the biochemical properties of two unrelated drugs, both of which act through binding at extracellular receptors, may be combined in the same molecule suggests a novel strategy for drug design. In principle, a combined effect of the two different substances that produce the same final effect (e.g., hypotension by adenosine agonists and by SP analogues) might occur in vivo. Adenosine analogues have analgesic properties, and the binary drug derived from substance P and adenosine agonists or antagonists might provide useful tools for probing interrelationships of SP pathways and sites for the antinociceptive action of adenosine.

Adenosine↗
PubMed1987

Evidence that a novel 8-phenyl-substituted xanthine derivative is a cardioselective adenosine receptor antagonist in vivo.

The ability of caffeine, enprofylline (3-propylxanthine), 8-phenyltheophylline, 8-p-sulphophenyl-theophylline, 8-(4'-carboxymethyloxyphenyl)-1,3-dipropylxanthine, and 8-(4'-carboxymethyloxyphenyl)-1,3-dipropylxanthine-2-aminoethyl amide (XAC) to antagonize the effects of an adenosine analogue, N-5'-ethylcarboxamidoadenosine, on heart rate and blood pressure in anesthetized rats was examined. The first five xanthine derivatives were equally active in antagonizing the two responses. By contrast, XAC was approximately 20 times more potent in antagonizing the heart rate response than the blood pressure response. Measurements of the concentration of XAC in plasma and brain indicate that it penetrates the central nervous system poorly. It is concluded that XAC is a cardioselective adenosine antagonist, and since adenosine is supposed to reduce heart rate via an effect on A1-receptors, and the blood pressure via A2-receptors, XAC may be a selective A1-adenosine receptor antagonist in vivo.

Adenosine↗
PubMed1987

Apparent affinity of some 8-phenyl-substituted xanthines at adenosine receptors in guinea-pig aorta and atria.

1 Some 8-phenyl-substituted, 1,3 dipropyl xanthines have previously been demonstrated to have a 20-400 fold greater affinity for A1 binding sites in rat CNS membranes than for A2 adenosine receptors in intact CNS cells from guinea-pigs. In the present study these compounds (1,3, dipropyl-8-phenylxanthine: DPPX; 1,3 dipropyl-8-(2 amino-4-chlorophenyl) xanthine: PACPX; 8-(4-(2-amino-ethyl)amino) carbonyl methyl oxyphenyl)-1,3-dipropylxanthine: XAC; and D-Lys-XAC) together with two that have not been reported to exhibit A1-receptor selectively (8-(p-sulphophenyl)theophylline: 8-PST; 8-(4-carboxy methyl oxyphenyl)-1,3-dipropylxanthine: XCC) have been evaluated as antagonists of the effects of 2-chloroadenosine in two isolated cardiovascular tissues. 2 The isolated tissues used were guinea-pig atria (bradycardic response) and aorta (relaxation), which are thought to possess A1 and A2 adenosine receptors, respectively. 3 All the xanthines antagonized responses evoked by 2-chloroadenosine in both tissues but did not affect responses evoked by acetylcholine (atria) or sodium nitrite (aorta). 4 The xanthines, 8-PST, XAC, D-Lys XAC, XCC and DPPX appeared to be competitive antagonists of the effects of 2-chloroadenosine, as Schild plot slopes did not differ significantly from unity. The 1,3-dipropyl substituted compounds had pA2 values from 6.5 to 7.4 and were more potent than the 1,3 dimethyl substituted 8-PST (pA2 4.9 to 5). 5 For individual xanthines, there was no difference between pA2 values obtained in the atria and in the aorta. 6 Responses evoked by 2-chloroadenosine in atria and aorta were antagonized to a similar degree by PACPX (1 microM). The agonist dose-ratio evoked by 10 microM PACPX was no greater than that evoked by 1 microM of the xanthine in both tissues. This was probably a consequence of the limited aqueous solubility of PACPX. 7. These results fail to demonstrate A, receptor selectivity for DPPX, XAC, D-Lys XAC or PACPX in tissues from the guinea-pig. The A, selectivity previously found for these compounds may therefore be due to their high affinity for binding sites in rat CNS cell membranes.

2-Chloroadenosine↗
PubMed1987

Interaction of dihydropyridine calcium channel agonists and antagonists with adenosine receptors.

We have confirmed our previous (Fredholm et al. 1986a) finding that the dihydropyridine calcium channel agonist Bay K 8644 can displace [3H]-R-PIA from its binding site, the adenosine A1-receptor. Bay K 8644 had an apparent Ki of 5.2 X 10(-6) M. The effect was shared by the two dihydropyridine calcium channel antagonists nifedipine and felodipine (Ki 4.2 and 8.7 X 10(-6) M, respectively). By contrast, two non-dihydropyridine calcium channel antagonists, verapamil and diltiazem, did not affect binding. Bay K 8644 displaced [3H]-R-PIA from its binding sites in a solubilized preparation. [3H]-XAC, a novel, potent A1-receptor antagonist ligand, was also displaced by the dihydropyridine compounds with a similar or slightly higher potency as the displacement of R-PIA. This suggests a direct interaction with the adenosine receptor rather than an effect on regulatory GTP-binding proteins. However, at 1 mumol/l neither Bay K 8644 nor nifedipine significantly attenuated cyclic AMP accumulation in rat hippocampi or the R-PIA-mediated adenylate cyclase inhibition. The results show that dihydropyridine compounds that act as agonists or antagonists on L-type calcium channels can also affect adenosine receptors. The potency of the compounds for this effect is much lower than their potency as calcium channel agonists or antagonists. The results may therefore be of more experimental than clinical significance.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1987

XAC, a functionalized congener of 1,3-dialkylxanthine, antagonizes A1 adenosine receptor-mediated inhibition of renin secretion in vitro.

Previous studies have shown that activation of A1 and A2 adenosine receptors leads to inhibition and stimulation respectively of renin secretion by rat renal cortical slices. In the present studies, rat renal cortical slices were incubated in the presence of adenosine deaminase, to destroy any adenosine released from the preparation. N6-cyclohexyladenosine (CHA) had a biphasic effect on renin secretion: submicromolar concentrations inhibited concentration-dependently, and there was an inflection in the dose-response curve near 1 microM CHA such that higher concentrations produced a concentration-dependent relative stimulation, which became an absolute stimulation (i.e., secretory rate was higher than control) at 50 microM. These findings are consistent with A1 and A2 adenosine receptor-mediated inhibition and stimulation of renin secretion, respectively. Xanthine amine congener ["XAC," 8-(4-((2-aminoethyl)-aminocarbonylmethyloxy)phenyl-1,3-dipropyl xant hine] has been shown by others to be a very potent adenosine receptor antagonist with selectivity for A1 receptors. It antagonized both CHA-induced inhibition (Ki approximately 2 x 10(-9) M) and CHA-induced stimulation (Ki approximately 5 x 10(-8) M) of renin secretion. Thus, XAC exhibited a 25-fold selectivity for CHA-induced inhibition of renin secretion in comparison with CHA-induced stimulation. In comparison with previous results, XAC is approximately 3 orders of magnitude more potent than theophylline. In conclusion, occupation of adenosine receptors can lead either to inhibition (A1 receptor-mediated) or stimulation (A2 receptor-mediated) of renin secretion, and XAC is a very potent and selective antagonist of CHA-induced changes in renin secretion.

Adenosine↗
PubMed1987

Further characterization of the renovascular effects of N6-cyclohexyladenosine in the isolated perfused rat kidney.

Previous studies have shown that activation of A1 adenosine receptors results in renal vasoconstriction at submicromolar concentrations of N6-cyclohexyladenosine (CHA) followed by relative vasodilation at higher concentrations. The present data confirm these findings and demonstrate that Na loading enhances the vasoconstrictor effects of CHA in the isolated rat kidney perfused at constant flow. Furthermore, adenosine receptor antagonism with both theophylline and the A1-selective antagonist, xanthine amine congener (8-[4-[(2-aminoethyl)-aminocarbonylmethyloxy]phenyl]-1, 3-dipropylxanthine), produced a rightward and apparently parallel shift in the dose response to CHA. Determination of the inhibitory constants for both antagonists revealed that xanthine amine congener was three orders of magnitude more potent than theophylline in antagonizing CHA-induced renal vasoconstriction. Other investigators have hypothesized that angiotensin II mediates adenosine-induced renal vasoconstriction. However, we have been able to show that A1 receptor activation can result in renal vasoconstriction in the isolated perfused rat kidney devoid of renin substrate. Moreover, a competitive inhibitor of angiotensin II (saralasin) failed to attenuate the hemodynamic effects of CHA at doses that completely blocked the effects of angiotensin II itself. Taken together, these data are consistent with the hypothesis that A1 receptor activation in the kidney leads to vasoconstriction, a response that is enhanced by Na loading, and that A1 adenosine receptors and angiotensin II receptors are separate and distinct biochemical entities. Independent activation of either receptor leads to renal vasoconstriction, which can be prevented by its respective antagonist.

Adenosine↗
PubMed1987

Adenosine receptors: development of selective agonists and antagonists.

Adenosine modulates a variety of physiological functions through interaction with A1 and A2 adenosine receptors, where agonists mediate inhibition and stimulation, respectively, of adenylate cyclase. In the cardiovascular system, A2 receptors mediate vasodilation and reduction in blood pressure, while A1 receptors mediate cardiac depression. The involvement of adenylate cyclase in these responses remains unresolved. Adenosine analogs in particular the N6-substituted compounds are more potent at A1 receptors than at A2 receptors. The subregion of the adenosine receptor that interacts with the N6-substituent is different for A1 and A2 receptors, particularly with respect to phenyl interactions, bulk tolerance and stereoselectivity. A series of para-substituted N6-phenyladenosines have been synthesized based on a "functionalized congener" approach in which a chemically reactive group, such as an amine or carboxylic acid, is introduced at the terminus of a chain. From the "functionalized congener" are synthesized a variety of conjugates each containing a common pharmacophore. Certain of the adenosine conjugates are highly selective for A1 receptors. Xanthines are classical antagonists for adenosine receptors for many of their pharmacological actions may be due to blockade of adenosine receptors. Caffeine and theophylline are virtually non-selective for A2 and A2 receptors. Replacement of the methyl groups of theophylline with n-propyl or larger alkyl groups yields xanthines with selectivity for A1 receptors, particularly when combined with an 8-phenyl moiety. Most 1,3-dialkyl-8-phenyl xanthines are very insoluble, but incorporation of polar aryl substituents, such as sulfo or carboxy to increase solubility, results in marked reduction in potency and selectivity. A new series of more hydrophilic 1,3-dipropyl-8-phenylxanthines has been synthesized using the "functionalized congener" approach. Certain conjugates of 8-[4-(carboxymethyloxy)phenyl 1]1,3-dipropylxanthine display A1 selectivity in biochemical and cardiovascular models. Certain analogs of caffeine in which the methyl group at the 1- or 7-position is replaced with a propargyl or propyl group display selectivity for A2 receptors. The profile of a series of adenosine analogs or of xanthine antagonists can be used to define the nature of adenosine receptors.

Adenosine↗
PubMed1987

A new high affinity, iodinated adenosine receptor antagonist as a radioligand/photoaffinity crosslinking probe.

A new high affinity antagonist photoaffinity crosslinking radioligand has been synthesized for use in studying adenosine receptors. This compound, PAPAXAC (8-[-4-[[[[[2-(4-aminophenylacetylamino)ethyl]amino]carbonyl]- methyl]oxy]phenyl]-1,3-dipropylxanthine), has been labeled with 125I by a chloramine T method. The radioligand [125I]PAPAXAC binds to A1 adenosine receptors from bovine cerebral cortex with high affinity (KD = 0.1 nM), appropriate stereoselectivity, and A1 adenosine receptor specificity. Binding is not perturbed by guanine nucleotides. Adenylate cyclase assays document that PAPAXAC is an antagonist capable of completely blocking the ability of N6-R-phenyl-2-propyladenosine (R-PIA) to inhibit adenylate cyclase activity via A1 adenosine receptors. [125I]PAPAXAC can be incorporated covalently into a peptide of Mr = 40,000 using the heterobifunctional crosslinking agent N-succinimidyl-6-(4'-azido-2'-nitrophenylamino)hexanoate. Covalent labeling can be inhibited with adenosine receptor ligands to demonstrate a potency series of R-PIA greater than S-PIA greater than NECA much greater than IBMX. Guanine nucleotides do not decrease covalent incorporation. These results suggest that antagonists such as [125I]PAPAXAC recognize the same A1 adenosine receptor-binding subunit as agonists, such as [125I]AZPNEA, which labels a similar Mr peptide with the same pharmacological potency series. This new antagonist photoaffinity crosslinking probe/radioligand should be of great utility in the molecular characterization of A1 adenosine receptors.

Adenylyl Cyclases↗
PubMed1987

A1- and A2-selective adenosine antagonists: in vivo characterization of cardiovascular effects.

Caffeine, a nonselective adenosine receptor antagonist, 7-methyl-1,3-dipropylxanthine, a purported A2 selective antagonist and a 1,3-dipropyl-8-phenylxanthine amine congener (XAC), an A1 selective antagonist, were evaluated for their in vivo selectivity at A1 vs. A2 adenosine receptors. Blockade of the negative chronotropic effect of bolus i.v. injections of 2-chloroadenosine, R-phenylisopropyladenosine and N-ethylcarboxamidoadenosine was utilized as an index of antagonism at A1 receptors; blockade of the hypotensive effect of the same series of adenosine agonists was used as an index of activity at A2 receptors. In addition, blockade of the potentiating effect of adenosine on the hypertensive and chronotropic effects of nicotine was studied to assess further the role of A1 and A2 adenosine receptors in this response. The potent antagonist XAC displayed considerable A1 selectivity as demonstrated by blockade of adenosine receptor-mediated bradycardia at doses 5- to 10-fold lower than those antagonizing adenosine receptor-mediated hypotension. XAC also selectively blocked potentiation by adenosine of the positive chronotropic effect of nicotine, at doses which had minimal effects on the enhancement of the hypertensive effect of nicotine. The caffeine homolog 7-methyl-1,3-dipropylxanthine exhibited A2 selectivity as demonstrated by prevention of adenosine receptor-mediated hypotension at doses which only minimally attenuated the bradycardiac effect of adenosine analogs. Caffeine displayed no selectivity for A1 vs. A2 adenosine receptors. The results indicate that selective analogs such as XAC and F-methyl-1,3-dipropylxanthine will be useful probes for investigation of receptors involved in the physiological functions of adenosine.

Adenosine↗