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N Substituted Xanthines
A Caffeine Analog Information File
by Jason Kennerly
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

       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.