Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027497 (nausea)
 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 (KD approximately 2 nM) (High-affinity PDE4, HPDE4). Rolipram is generally moderately or weakly active (IC50-200 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 clincial evaluation.
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PMID:Proposal for pharmacologically distinct conformers of PDE4 cyclic AMP phosphodiesterases. 921 22

Inhibitors of PDE4 (cAMP-specific phosphodiesterase) induce side effects, including nausea and emesis, that limit their therapeutic potential. We investigated the function of two catalytically active conformations of PDE4 (a low-affinity conformer detected by conventional cAMP hydrolytic activity and a high-affinity conformer detected by [(3)H]rolipram binding) in neuronal cells. We assessed enhancement of beta-adrenoceptor-mediated cAMP accumulation in cortical neurons in vitro by eleven PDE4 inhibitors with diverse biochemical profiles. The compounds tested have a wide inhibition range of PDE4 catalytic activity and [(3)H]rolipram binding. Inhibition potency for PDE4 catalytic activity and [(3)H]rolipram binding for each compound was different. Potency in augmentation of cAMP correlated significantly with the inhibitory effect on [(3)H]rolipram binding, but not with that against PDE4 catalytic activity. On the other hand, the inhibitory effect on proliferation of T-lymphocytes of the same PDE4 inhibitors correlated both with inhibition of PDE4 catalytic activity and with inhibition of [(3)H]rolipram binding. These findings indicate that the high affinity PDE4 conformer exists at a high level in cortical neurons and is important in the regulation of cAMP. Furthermore, the relative contributions of the two PDE4 conformers in cell function may cause different PDE4 inhibitor effects on cortical neurons and T-lymphocytes.
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PMID:Differential effects of PDE4 inhibitors on cortical neurons and T-lymphocytes. 1827 53