Proposal for Pharmacologically Distinct Conformers of PDE4 Cyclic AMP Phosphodiesterases

• Published in: Cellular Signalling Vol. 9; no. 3; pp. 227 - 236
• Main Authors: Souness, John E, Rao, Sudha
• Format: Book Review Journal Article
• Language: English
• Published: England Elsevier Inc 01.05.1997
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Binding Sites; cAMP; Conformers; Cyclic AMP; Cyclic Nucleotide Phosphodiesterases, Type 4; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Phosphodiesterase; Phosphoric Diester Hydrolases - chemistry; Phosphoric Diester Hydrolases - metabolism; Protein Conformation; Rolipram; RP 73401; TNFα, tumour necrosis factor alpha; RNPDE4; Conformers; Staphylococcal aureus enterotoxin A, Staph. A; O 2 −, superoxide anion; cAMP; PGE 2, prostaglandin E 2; MBP, major basic protein; HPDE4, high-affinity PDE4; Rattus norvegicus PDE4; Rolipram; V/GSH, vanadyl/glutathione complex; HARBS, high- affinity rolipram binding site; IBMX, 3-isobutyl-1-methylxanthine; LPS, lipopolysaccharide; RP 73401; ECP, eosinophil cationic protein; EDN, eosinophil-derived neurotoxin; IL-2, interleukin-2; PDE4–cAMP-specific phosphodiesterase; LPDE4, low- affinity PDE4; LTB 4, leukotriene B 4; Phosphodiesterase; HSPDE4, Homo sapiens PDE4
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/S0898-6568(96)00173-8

cAMP-specific phosphodiesterase inhibitors display a range of activities in vitro and in vivo which suggest they may be useful in the treatment of inflammatory diseases. However, these compounds elicit a number of side-effects which may limit their therapeutic potential. Certain side-effects of PDE4 inhibitors such as emesis and gastric acid secretion are associated with their actions at a high-affinity rolipram binding site (HARBS). In contrast, a number of anti-inflammatory actions of PDE4 inhibitors are better correlated with inhibition of PDE4 catalytic activity than with displacement of [ 3H] rolipram from HARBS. This suggests that native PDE4s in different cell-types can be discriminated pharmacologically. Although known to be associated with PDE4, the nature of HARBS is uncertain. The majority of evidence suggests it represents particular conformational states of PDE subtypes with which rolipram interacts with high potency (K D∼2 nM) (High-affinity PDE4, HPDE4). Rolipram is generally moderately or weakly active (IC 50-200 nM-2000 nM) in inhibiting catalytic activity of the majority of crude, partially-purified or recombinant PDE4 preparations (Low-affinity PDE4, LPDE4). Solubilization or V/GSH treatment of particulate eosinophil PDE4, cAMP-dependent kinase activation of RNPDE4D3 and membrane association of HSPDE4A4 increase the potencies of some (e.g., rolipram) but not other (e.g., trequinsin) inhibitors. In eosinophils, the changes in enzyme properties brought about by solubilization result in a close correlation between the potency order of compounds in inhibiting cAMP hydrolysis and displacing [ 3H] rolipram from HARBS. The identification of distinct pharmacological PDE4 forms may have therapeutic consequences since it may be possible to synthesize potent inhibitors of LPDE4 with low affinity for HARBS which should, theoretically, be less emetic. Most inhibitors synthesized to date (rolipram, denbufylline nitraquazone, etc.) display high-affinity for HARBS but are much weaker in inhibiting cAMP hydrolysis. Other compounds (RP 73401, trequinsin, CDP 840) display slightly higher potency against LPDE4 or do not discriminate between the two putative PDE4 forms. Recently, inhibitors have been synthesized which are considerably more active against LPDE4 than HPDE4. Such compounds with appropriate pharmacokinetic properties may retain anti-inflammatory activity but have a reduced capacity to cause nausea and emesis and, consequently, have a wider therapeutic window than compounds currently undergoing clinical evaluation.