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

Abstract

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.