Studies on the synthesis of compounds related to adenosine-3',5'-cyclic phosphate. VI. Synthesis and cardiac effects of N6,N6,2'-O-trialkyl-, N6,2'-O-dialkyl-, and 2'-O-alkyladenosine-3',5'-cyclic phosphates.
The alkylation of adenosine-3',5'-cyclic phosphate (cAMP, 1) with alkyl bromides was investigated and various new alkylated cAMP derivatives, N6,N6,2'-O-trialkyl cAMPs (2), N6,2'-O-dialkyl cAMPs (3) and 2'-O-alkyl cAMPs (4), were prepared by a one step reaction without the introduction of a protecting group into 1. Compounds (2) were synthesized from 1 by treatment with alkyl bromides in the presence of NaH or potassium tert-butoxide in dimethyl sulfoxide. Compounds (3) were also synthesized from 1 under conditions similar to those of the synthesis of 2 except for the use of MeONa as a base. Compounds (4) were prepared from 1 by treatment with alkyl bromides in the presence of 18-crown-6 in dioxane-aqueous KOH solution. N6,2'-O-Dibenzyl cAMP (3e) was obtained from 1 by the same method as the preparation of 4. These new alkylated derivatives were evaluated for cardiotonic activity in vitro. Some of them showed weak positive inotropic effects and strong negative chronotropic effects. Thus, the presence of the 2'-hydroxyl group seemed to be essential for the appearance of potent positive inotropic activity caused by cAMP derivatives.
Kataoka
S
S
Research and Development Division, Kikkoman Corporation, Chiba, Japan.
Imai
J
J
Yamaji
N
N
Kato
M
M
Kawada
T
T
Imai
S
S
D000818:Animals; D002317:Cardiovascular Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects
D002317:Cardiovascular Agents; D000242:Cyclic AMP