Effect of some new cAMP analogs on cAMP-dependent protein kinase isoenzymes.

1.1. Ten new cAMP analogs were synthesized by replacing the purine ring with indazole, benzimidazole or benztriazole and/or their nitro and araino derivatives.2.2. Each analog proved effective in activating cAMP-dependent protein kinase I (PK-I) purified from rabbit skeletal muscle and cAMP-dependent protein kinase II (PK-II) from bovine heart and chasing 8-[3H]cAMP bound to regulatory subunits in the half-maximal effective concentrations of 2 × 10−8-8 × 10−6 M.3.3. The N-1-β-d-ribofuranosyl-indazole-3′5′-cyclophosphate(I) proved a very poor chaser and activator of both isoenzymes, but when indazole was attached at its N-2 to ribose (IV) or when its H at C-4 (equivalent to the position of amino-group in adenine) was substituted by an amino-(III) or especially nitro-group (II) its efficiency was dramatically increased.4.4. Analogs containing benztriazole ring proved as powerful as cAMP irrespective of the presence of substituents (VII–X).5.5. Benzimidazole derivatives with amino-(VI) or nitro-group (V) activated PK-II 3 and 20 times better than PK-I.6.6. Attaching of ribose to N-2 of indazole or benztriazole increased the affinity to PK-II 10 and 4 times, respectively.7.7. Chasing efficiency of cAMP analogs at half-saturating [3H]cAMP tended to correlate with activating potency only for PK-I but at saturating [3H]cAMP concentration for both isoenzymes.8.8. On the basis ofsynergistic activation with 8-Br-cAMP a site 2-selective binding ofnitro-benzimidazole (V) and unsubstituted benztriazole (VII) derivatives to PK-II is suggested.