2. • GENERAL FUNCTION OF PHOSPHODIESTERASES
• ATP ADENYL CYCLASE CYCLIC AMP PROTEIN KINASE A PHOSPHORYLATION
INVOLVED IN REGULATION OF CELLULAR FUNCTION ,APOPTOSIS,IMMUNE
RESPONSE,CARDIAC MUSCLE CONTRACTIONS,CHANGE IN GENE
EXPRESSION,CELL METABOLISM
• CYCLIC AMP PDE 5’AMP
GTP GUANYLYL CYCLASE CYCLIC GMP PROTEIN KINASE G PHOSPHORYLATION
• INVOLVED IN REGULATION OF CELLULAR FUNCTION ,APOPTOSIS,IMMUNE
RESPONSE,CARDIAC MUSCLE CONTRACTIONS,CHANGE IN GENE EX
• CYCLIC GMP PDE 5’GMP
3. NOMENCLATURE OF PDE
FAMILY OF 21 GENES ,TOTAL 11 FAMILIES,60 ISOFORMS
EX: P D E 4 D 2
FAMILY
GENE
VARIANT
WIDELY DISTRIBUTED THROUGHOUT BODY ,ISOFORM SPECIFIC TISSUE
CONCENTRATIONS.
PDE ROLE :ANTI-INFLAMMATORY ,ANTI DEPRESSANT, VASODILATORS,SM
RELAXANT,ANTI-THROMBOTICS.
4. ROLE OF PDE IN ERECTILE DUYSFUNCTION
SEXUAL STIMULATION RELEASE OF NITRIC OXIDE BY CAVERNOSA
CYCLASE
PDE INHIBITOR :SILDENAFIL
,TADALAFIL ,
VERDENAFIL CGMP ACTIVE
PDE
5’AMP DECREASED CELLULAR
LEVEL OF CALCIUM
RELAXATION OF SMOOTH MUSCLE
ERECTION OF PENIS
5. SPECIFIC PDE
CYCLIC AMP CYCLIC GMP
PDE4,PDE8,PDE7 PDE5 PDE6,PDE9
PDE1,PDE2,PDE3,PDE10,PDE11 CAN ACT ON BOTH
CYCLIC AMP AND CYCLIC GMP
6. ROLE OF PDE ON PLATLETS
CYCLIC AMP CILOSTAZOL CYCLIC GMP
PDE3A PDE3A
PLATLET INHIBITION PLATLET INHIBITION
INHIBITION OF PDE3A CAUSE INCREASE LEVEL OF
CYCLIC AMP AND CYCLIC GMP LEADS TO ANTIPLATLET
ACTION, ANTITHROMBOTIC, VASODILATORY EFFECT.
7. SELECTIVITY
THE SPECIFICITY OF PDE IS DERIVED FROM H-BOND
WITHIN ACTIVE SITE WHICH STRONGLY FAVOURS EITHER
cAMP SPECIFIC OR cGMP CONFORMATION.THESE
CONFORMATION DIFER BY ROTATION ABOUT Cᴕ -CΔ
BOND OF GLUTAMINE.
A PLANAR RING STRUCTURE IS HELD TIGHTLY ON ACTIVE SITE
BY INTERACTION WITH HYDROPHOBIC RESIDUES THAT LINE THE
NUCLEODTIDE BINDING POCKET ,FACILITATING HYDROGEN
BOND INTERACTION WITH INVARIANT GLUTAMINE WHICH IS
ESSENTIAL FOR NUCLEOTIDE RECOGNITION AND
SELECTIVITY.
8. CARDIAC SELECTIVE DRUGS
AMRINONE AND MILRINONE USED IN HEART
FAILURE ACTING ON PDE3 ENZYME LEADING
TO POSITIVE INOTROPIC AND LUSITROPIC
EFFECT AND VASODILATION .
DECREASE PULMONARY CAPILLARY WEDGE
PRESSURE AND INCREASE CARDIAC OUTPUT.
9. REFERENCES
THOMAS L. LEMKE, DAVID A. WILLIAMS,
VICTORIA F. ROCHE ,S. WILLIAM ZITO
FOYE’S PRINCIPLES OF MEDICINAL CHEMISTRY
SIXTH EDITION
