The lipophilicity of cyclic nucleotides has a major impact on their cell membrane permeability. In order to make biological results with different cyclic AMP and cyclic GMP analogs really comparable, for each new analog synthesized, the corresponding lipophilicity is determined by a new method 1, 2
On the bottom you will find both, cyclic AMP and cyclic GMP, respectively, as standards (value 1). Corresponding analogues are positioned according to their relative lipophilicity on a logarithmic scale.
cAMP analogues are listed on the left, while cGMP derivatives are found on the right side. As a rule, cGMP analogues are generally more polar than the corresponding cAMP structures (exception: DB-cGMP & N2-MB-cGMP). Direct cross comparison of cAMP with cGMP analogues is possible within the graph. The higher a compound is listed in the ranking, the better its membrane permeability will be. A click on the compounds name will link to the corresponding catalogue entry. For structures not listed, please inquire.
Q.: Is 8- bromo cyclic GMP (8-Br-cGMP) a structure with high membrane permeability?
A.: No, not really. It is much more non-polar compared to cGMP, but its overall lipophilicity is only a little better compared to cAMP (which is supposed to be rather badly permeant).
Q.: Which cAMP and which cGMP analogue has the highest lipophilicity in the ranking?
A.: It is 8-CPT-6-Phe-cAMP and Sp-8-pCPT-PET-cGMPS, respectively.
Q.: Which is the ranking order for the lipophilicity of the cAMP antagonists ( Rp-cAMPS analogues)?
A.: Rp-8-OH-cAMPS (0.75 x) < Rp-cAMPS (1.3 x) < Rp-8-Br-cAMPS (2.4 x) << Rp-8-CPT-cAMPS (42 x). In brackets: Corresponding factors compared to the standard cyclic AMP (1x).
Relative Lipophilicity Scale |
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cyclic AMP Analogues |
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cyclic GMP Analogues |
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---- |
800 |
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8-CPT-6-Phe-cAMP------------------------ |
400 |
---- |
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---------------- Sp-8-pCPT-PET-cGMPS |
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---- |
700 |
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---- |
600 |
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300 |
---- |
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---------------- Rp-8-pCPT-PET-cGMPS |
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------------------------- 8-pCPT-PET-cGMP |
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---- |
500 |
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---- |
400 |
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200 |
---- |
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---- |
300 |
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100 |
---- |
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---- |
200 |
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--------------------- Sp-8-Br-PET-cGMPS |
Sp-8-pCPT-2'-O-Me-cAMPS ------------- |
90 |
---- |
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80 |
---- |
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Sp-5,6-DCl-cBIMPS ------------------------- |
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6MAH-cAMP ---------------------------------- |
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70 |
---- |
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8-CPT-2'-O-Me-cAMP---------------------- |
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Rp-8-HA-cAMPS ----------------------------- |
60 |
---- |
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--------------------- Rp-8-Br-PET-cGMPS |
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------------------------------- 8-Br-PET-cGMP |
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8-HA-cAMP------------------------------------- |
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Sp-8-CPT-cAMPS --------------------------- |
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5,6-DCl-cBIMP-------------------------------- |
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8-pMeOPT-2'-O-Me-cAMP---------------- |
50 |
---- |
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---- |
100 |
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---- |
90 |
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Rp-8-CPT-cAMPS --------------------------- |
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---- |
80 |
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40 |
---- |
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------------------------ Sp-8-pCPT-cGMPS |
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6-MBC-cAMP ---------------------------------- |
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---- |
70 |
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8-CPT-cAMP------------------------------- |
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------------------------ Rp-8-pCPT-cGMPS |
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8-MANT-cAMP --------------------------------- |
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------------------------------------------ DB-cGMP |
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---- |
60 |
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30 |
---- |
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---------------------------------- 8-pCPT-cGMP |
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Rp-8-Br-MB-cAMPS ------------------------ |
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---- |
50 |
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---------------------------------------- PET-cGMP |
8-BT-cAMP ------------------------------------- |
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5,6-DM-cBIMP --------------------------------- |
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6-Phe-cAMP ----------------------------------- |
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8-MABA-cAMP-------------------------------- |
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6-Bn-cAMP ------------------------------------- |
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DB-cAMP --------------------------------------- |
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---- |
40 |
------------------------------------ 8-APT-cGMP |
Sp-8-PIP-cAMPS ----------------------------- |
20 |
---- |
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8-pHPT-2'-O-Me-cAMP-------------------- |
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---- |
30 |
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Rp-8-PIP-cAMPS ---------------------------- |
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8-NBD-cAMP ---------------------------------- |
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8-PIP-cAMP ------------------------------------ |
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Rp-2'-O-MB-cAMPS ------------------------ |
10 |
---- |
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---- |
20 |
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9 |
---- |
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----------------------------------- 8-NBD-cGMP |
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----------------------------------- MANT-cGMP |
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8 |
---- |
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7 |
---- |
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2'-O-MB-cAMP-------------------------------- |
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------------------------------------ N2-MB-cGMP |
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6-Bnz-cAMP ----------------------------------- |
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6 |
---- |
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---- |
10 |
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5 |
---- |
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---- |
9 |
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---- |
8 |
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4 |
---- |
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Sp-8-Br-cAMPS------------------------------ |
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Sp-8-Cl-cAMPS ------------------------------- |
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---- |
7 |
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N6-MB-cAMP---------------------------------- |
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8-Br-2'-O-Me-cAMP------------------------- |
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---- |
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3 |
---- |
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--------------------------------- 2'-O-MB-cGMP |
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---- |
5 |
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Rp-8-Br-cAMPS ------------------------------ |
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------------------------------- Sp-8-Br-cGMPS |
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Rp-8-Cl-cAMPS ------------------------------ |
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2-Aza-ε-cAMP -------------------------------- |
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---- |
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2 |
---- |
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8-N3-cAMP ------------------------------------- |
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8-Br-cAMP -------------------------------------- |
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ε-cAMP ------------------------------------------ |
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8-AHA-cAMP ---------------------------------- |
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2'-O-Me-cAMP --------------------------------- |
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6-Cl-cPuMP ------------------------------------ |
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2-Cl-cAMP -------------------------------------- |
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------------------------------ Rp-8-Br-cGMPS |
8-Cl-cAMP -------------------------------------- |
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Sp-cAMPS -------------------------------------- |
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---- |
3 |
------------------------------------------ 2'-dcGMP |
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Rp-cAMPS ------------------------------------------------ |
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---------------------------------------- 8-Br-cGMP |
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cTuMP ------------------------------------------------------- |
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Sp-8-OH-cAMPS ------------------------------------- |
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(8-ADOA-cAMP) ----------------------------------------- |
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8-MA-cAMP ---------------------------------------------- |
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cyclic AMP ---------------- |
1 |
---- |
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---- |
2 |
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( Standard ) |
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0.9 |
---- |
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--------------------------------------- Sp-cGMPS |
cPuMP ------------------------------------------------------- |
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---------------------------------- 2'-O-Me-cGMP |
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0.8 |
---- |
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2'-dcAMP -------------------------------------------------- |
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Rp-8-OH-cAMPS ------------------------------------- |
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8-OH-cAMP ---------------------------------------------- |
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0.7 |
---- |
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------------------------------------ 8-AET-cGMP |
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--------------------------------------- Rp-cGMPS |
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0.6 |
---- |
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---- |
1 |
----------------- cyclic GMP |
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0.5 |
---- |
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( Standard ) |
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---- |
0.9 |
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--------------------------------- 1-NH2-cGMP |
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References:
H.- G. Genieser, Structure and Function in Biological Systems, poster presentation, Würzburg, Germany, 1993: "Lipophilic Ranking of Biochemically and Pharmacologically Important Cyclic Nucleotide Analogues" |
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Kraß, J.; Jastorff, B.; Genieser, H.-G.; Anal. Chem., 69, 2575 - 2581 (1997): |