cyclic-gmp and griseolic-acid

Topics: Adenosine; Animals; Cyclic AMP; Cyclic GMP; Drug Design; Phosphodiesterase Inhibitors; Structure-Activity Relationship

Synthetic analogs of the natural product griseolic acid in which a guanine base is substituted for the adenine have been prepared. The best of these compounds inhibits a cyclic guanosine 3',5'-monophosphate (cGMP) phosphodiesterase preparation with an IC50 of 0.34 microM but is a very weak inhibitor of a cyclic adenosine 3',5'-monophosphate (cAMP) phosphodiesterase. An exploration of stereochemistry indicates that the configuration of the carboxylic acids and the ring fusion in the inhibitors is important for potent cGMP PDE inhibition. PDE inhibition is not sensitive to the presence of the 2' or 4' oxygen atoms in the ribose, but inhibition is decreased when the 3' oxygen is removed. A selected group of analogs in which a monocarboxylic acid is present are poor inhibitors. The structure-activity relationship is consistent with the carboxylic acid functionality acting as a mimetic for the phosphate anion in cGMP. This concept is supported by a conformational analysis of two of the inhibitors.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; 3',5'-Cyclic-GMP Phosphodiesterases; Adenosine; Carboxylic Acids; Computer Simulation; Cyclic GMP; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Molecular Structure; Structure-Activity Relationship

The effects of griseolic acid (GA), a cyclic-AMP phosphodiesterase (PDE) inhibitor, and its 8'-pivaloyloxymethyl (POM) ester on intraocular pressure (IOP) in rabbits were investigated. When 50 microliters of 1 and 2% GA POM ester solutions were topically applied to one eye in normal rabbits, significant IOP decreases were detected at 2 hrs and at 1 to 5 hrs, respectively. Other than ocular hypotension, no other ocular effects were detected locally even after administration of 2% GA POM ester. A more marked reduction in IOP occurred after the intravitreal injection of the GA POM ester. IOP was also reduced when GA was used in an intravitreal injection but not when it was topically applied. The difference in permeability between GA and GA POM ester across the corneal epithelium may explain why GA failed to reduced IOP following topical administration. GA and the GA POM ester inhibited cAMP PDE in rabbit ciliary body at low concentrations, the I50 being 0.075 microM and 2.4 microM, respectively, with 0.25 microM cAMP as substrate. GA and the GA POM ester markedly increased cAMP levels in vitro in iris-ciliary body specimens. Possibly, GA POM ester or its analogues may represent a new mechanistic class of ocular hypotensive agents.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Adenosine; Animals; Ciliary Body; Cornea; Cyclic GMP; Intraocular Pressure; Iris; Male; Permeability; Rabbits; Vitreous Body

Griseolic acid inhibited cAMP phosphodiesterase (PDE) at low concentrations, the I50 being of the order of 0.01-0.1 microM. Administration of griseolic acid to rats increased the cAMP level in liver and plasma several-fold. It increased glycogen degradation in mouse liver and stimulated lipolysis in isolated rat fat cells. Griseolic acid did not block the adenosine-elicited accumulation of cAMP in guinea pig brain slices. It had no effect on cAMP-dependent protein kinase from rat liver nor on the adenyl cyclase from rat brain.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Adenosine; Adipose Tissue; Animals; Blood Glucose; Brain; Cerebral Cortex; Cricetinae; Cyclic AMP; Cyclic GMP; Guinea Pigs; In Vitro Techniques; Kinetics; Lipolysis; Liver; Liver Glycogen; Male; Mice; Mice, Inbred Strains; Rats; Rats, Inbred Strains