N Substituted Xanthines
A Caffeine Analog Information File
Sep 22, 1995
alt.drugs.chemistry, sci.med.psychobiology
Here is the information I have gathered so far on caffeine analogs, with abstracts as references. Any other information on any of these compounds, or other n-substituted xanthines would be of great interest to me, especially concerning the use of such compounds in humans ["tasting"]
ASCII DEPICTIONS, SUMMARY INFO
chart:
A1: Activity at A1 relative to caffeine
A2: Activity at A2 relative to caffeine
PDE: PDE inhibiton reletive to caffeine
Action: Depressant or Stimulant of behaviour
ASCII DEPICTIONS, SUMMARY INFO
chart:
A1: Activity at A1 relative to caffeine
A2: Activity at A2 relative to caffeine
PDE: PDE inhibiton reletive to caffeine
Action: Depressant or Stimulant of behaviour
O CH3 O
|| | || H
H3C C N{7} H3C C N
\ / \ / \ \ / \ / \
{1}N || \ N || \
| || // | || //
//\ / \// //\ / \//
O N{3} N O N N
| |
CH3 CH3
Caffeine Theophylline
A1: 1 A1: ?
A2: 1 A2: ?
PDE: is PDE: ?(less?)
Action: Stimulant Action: weak Stimulant
--------------------------------------------------------------------------------------------------------------------------
CH
|||
CH H2C--C
||| |
C O CH3 O CH2
| || | || |
H2C C N H3C C N
\ / \ / \ \ / \ / \
N || \ N || \
| || // | || //
//\ / \// //\ / \//
O N N O N N
| |
CH3 CH3
1-Proparagyl 3,7-Dimethyl 7-Proparagyl 1,3-Dimethyl
Xanthine Xanthine
A1: .5 A1: .5
A2: 4 to 7 A2: 3 to 4
PDE: less PDE: ?
Action: Stimulant Action: ?
--------------------------------------------------------------------------------------------------------------------------
CH CH
||| |||
O CH3 C O H2C--C
|| | | || |
H3C C N H2C C N
\ / \ / \ \ / \ / \
N || \ N || \
| || // | || //
//\ / \// //\ / \//
O N N O N N
| |
C--CH2 C--CH2
||| |||
CH CH
3-Proparagyl 1,7-Dimethyl 1,3,7-Triproparagyl
Xanthine Xanthine
A1: ? high in A1: ? high in
A2: ? general A2: ? general
PDE: less PDE: less
Action: Stimulant Action: Stimulant
--------------------------------------------------------------------------------------------------------------------------
O O CH2-CH2-CH3
|| H || |
H3C C N H3C-H2C-H2C C N
\ / \ / \ \ / \ / \
N || \ N || \
| || // | || //
//\ / \// //\ / \//
O N N O N N
| |
C CH2-CH2-CH2
/ \
H3C CH2-CH3
IBMX 1,3,7-Tripropyl Xanthine
A1: ? A1: higher than 1,3,7 triproparagyl-x!
A2: ? A2: higher ""
PDE: high PDE: higher ""
Action: Depressant Action: Depressant [due to PDE]
--------------------------------------------------------------------------------------------------------------------------
_____
/ _ \
O CH2-< (_) > O CH3
|| | \_____/ || |
H3C C N H3C-H2C-H2C C N
\ / \ / \ \ / \ / \
N || \ N || \
| || // | || //
//\ / \// //\ / \//
O N N O N N
| |
C CH3
/ \
H3C CH2-CH3
7-Benzyl-IBMX 1-Propyl 3,7-Dimethyl Xanthine
A1: ? (high) A1: 1.4
A2: ? (high) A2: >10
PDE: ? (high) PDE: ?
Action: weak Stimulant Action: ?
--------------------------------------------------------------------------------------------------------------------------
CH
|||
O CH3 O H2C--C
|| | || |
H3C-H2C-H2C C N H3C-H2C-H2C C N
\ / \ / \ \ / \ / \
N || \ N || \
| || // | || //
//\ / \// //\ / \//
O N N O N N
| |
CH2-CH2-CH3 CH2-CH2-CH3
1,3-Dipropyl 7-Methyl 1,3-Dipropyl 7-Proparagyl
Xanthine Xanthine
A1: 8 A1: ~100
A2: 40 A2: ~100
PDE: ? PDE: ?
Action: ? Action: ?
--------------------------------------------------------------------------------------------------------------------------
O CH3 O H2C--CH==CH2
|| | || |
H3C C N H3C C N
\ / \ / \ \ / \ / \
N || \ N || \
| || // | || //
//\ / \// //\ / \//
O N N O N N
| |
CH3 CH3
3,7-Dimethyl 1-Propyl 7-allyl 1,3-dimethyl
Xanthine Xanthine
A1: ? A1: ?
A2: more than A1 A2: more than A1
PDE: ? PDE: ?
Action: ? Action: ?
--------------------------------------------------------------------------------------------------------------------------
***Abstracts of articles where above information was obtained*** CAFFEINE ANALOGS: STRUCTURE-ACTIVITY RELATIONSHIPS AT ADENOSINE RECEPTORS. Daly JW; Hide I; Muller CE; Shamim M Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Md. Pharmacology 42: 309-21 (1991) Abstract Caffeine and analogs that contain ethyl, propyl, allyl, propargyl and other substituents in place of methyl at 1-, 3- and 7-positions were antagonists at the two major classes (A1 and A2) of adenosine receptors. Potency at both receptors increased as methyls were replaced with larger substituents. Certain analogs with only one of the three methyl groups of caffeine replaced by larger substituents were somewhat selective for A2 receptors. None of the analogs were particularly selective for A1 receptors. The presence of polar entities in the substituent at the 1- or 7-position was poorly tolerated at adenosine receptors. Activity of caffeine analogs at A1 and A2 adenosine receptors in a variety of systems and cell types is presented and summarized. *** ANALOGS OF CAFFEINE: ANTAGONISTS WITH SELECTIVITY FOR A2 ADENOSINE RECEPTORS. Ukena D; Shamim MT; Padgett W; Daly JW Life Sci 39: 743-50 (1986) Abstract Several analogs of caffeine have been investigated as antagonists at A2 adenosine receptors stimulatory to adenylate cyclase in membranes from rat pheochromocytoma PC12 cells and human platelets and at A1 adenosine receptors inhibitory to adenylate cyclase from rat fat cells. Among these analogs, 1-propargyl-3,7-dimethylxanthine was about 4- to 7-fold and 7-propyl-1,3-dimethylxanthine about 3- to 4-fold more potent than caffeine at A2 receptors of PC12 cells and platelets. At A1 receptors of fat cells, both compounds were about 2-fold less potent than caffeine. These caffeine analogs have an A1/A2 selectivity ratio of about 10-20 and are the first selective A2 receptor antagonists yet reported. The results may provide the basis for the further development of highly potent and highly selective A2 adenosine receptor antagonists. *** CAFFEINE AND THEOPHYLLINE ANALOGUES: CORRELATION OF BEHAVIORAL EFFECTS WITH ACTIVITY AS ADENOSINE RECEPTOR ANTAGONISTS AND AS PHOSPHODIESTERASE INHIBITORS. Choi OH; Shamim MT; Padgett WL; Daly JW Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland 20892. Life Sci 43: 387-98 (1988) Abstract The behavioral stimulant effects of xanthines, such as caffeine and theophylline, appear to involve blockade of central adenosine receptors. However, 3-isobutyl-1-methylxanthine (IBMX), a potent phosphodiesterase (PDE) inhibitor, produces behavioral depression. The effects of caffeine analogs on open field behavior of mice and potencies as antagonists of adenosine receptors and as inhibitors of three classes of brain PDE have been compared. 1,7-Dimethyl-3-propargylxanthine, 1,3,7-tripropargylxanthine, and 3,7-dimethyl-1-propargylxanthine, which have high affinity for adenosine receptors and weaker activity as PDE inhibitors, all increase behavioral activity. In contrast, 1,3,7-tripropylxanthine, a more potent inhibitor of the brain calcium-independent (Ca-indep) PDEs than 1,3,7-tripropargylxanthine, produces behavioral depression, even though both analogues are potent adenosine receptor antagonists. 7-Benzyl-IBMX, an active receptor antagonist and selective inhibitor of a brain calcium-dependent (Ca-dep) PDE, produces a slight behavioral activation. Xanthines that are potent adenosine receptor antagonists and relatively weak inhibitors of the Ca-indep PDEs reverse the depressant effects of N6-cyclohexyladenosine, while xanthines, such as 1,3,7-tripropylxanthine, that are potent inhibitors of the Ca-indep PDEs, do not. The results suggest that the behavioral effects of xanthines may be determined primarily by relative activity as adenosine receptor antagonists and as inhibitors of brain Ca-indep PDEs. *** ANALOGUES OF CAFFEINE AND THEOPHYLLINE: EFFECT OF STRUCTURAL ALTERATIONS ON AFFINITY AT ADENOSINE RECEPTORS. Daly JW; Padgett WL; Shamim MT J Med Chem 29: 1305-8 (1986) Abstract A variety of analogues of caffeine and theophylline in which the 1-,3-, and 7-methyl substituents have been replaced with n-propyl, allyl, propargyl, and isobutyl and, in a few cases, with chloroethyl, hydroxyethyl, or benzyl were assessed for potency and selectivity as antagonists at A1- and A2-adenosine receptors in brain tissue. Caffeine and theophylline are nonselective for these receptors. Nearly all of the 22 analogues of caffeine are more potent than caffeine itself at adenosine receptors. Replacement of the 1-methyl moiety with n-propyl, allyl, or propargyl substituent has little effect on potency at the A1 receptor while enhancing potency about 7- to 10-fold at the A2 receptor. 3,7-Di-methyl-1-propylxanthine is only slightly (1.4-fold) more potent than caffeine at the A1 receptor while being 10-fold more potent at the A2 receptor. 1,3-Di-n-propyl-7-methylxanthine is also selective for the A2 receptor, being 8-fold more potent than caffeine at the A1 receptor and 40-fold more potent at the A2 receptor. A number of other caffeine analogues including 3,7-dimethyl-1-n-propylxanthine, 7-allyl-1,3-dimethylxanthine, and 1,3-dimethyl-7-propargylxanthine are also somewhat selective for the A2 receptor. The most potent caffeine analogue was 1,3-di-n-propyl-7-propargylxanthine, which was about 100-fold more potent than caffeine at both A1 and A2 receptors. The 10 theophylline analogues were relatively nonselective except for the 1-ethyl analogue and the 1,3-diallyl analogue, which were selective for the A2 receptor, and the 1,3-di-n-propyl, 1,3-diisobutyl, and 1,3-dibenzyl analogues, which were somewhat selective for the A1 receptor. 1,3-Di-n-propylxanthine was 20-fold more potent than theophylline at the A1 receptor and 5-fold more potent at the A2 receptor. *** ADENOSINE RECEPTORS: DEVELOPMENT OF SELECTIVE AGONISTS AND ANTAGONISTS. Daly JW; Jacobson KA; Ukena D Prog Clin Biol Res 230: 41-63 (1987) Abstract 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.