Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied the effect some drugs that participate in the Ca2+/ calmodulin system have on the progesterone (P) facilitation of lordosis behavior in ovariectomized estradiol (E2) primed rats. We injected rats 44 h after E2 priming with 2 mg P together with various dosages of one of the following compounds: pentobarbital, trifluoperazine (TPZ), promethazine (PMZ), Chlorpromazine (CPZ), haloperidol (HAL), pimozide (PIM), and verapamil (VER). Then 4 h after treatment, animals were tested for sexual behavior, expressed as the lordosis quotient (LQ). All drugs at 4 mg/kg or higher inhibited lordosis, but only HAL, PIM, and VER were active at 1 mg/kg. The maximum level of activity was shown by PIM, although at the dose of 8 mg/kg no statistical differences were found between this compound and TPZ or HAL. Pentobarbital (25 mg/kg) showed no significant difference from saline-treated controls. The activity of the tested drugs on the facilitation of sexual behavior appears to be related to their efficiency as inhibitors of calmodulin (CaM)-dependent phosphodiesterase and as ligands for the Ca(2+)-CaM complex.
 ...
PMID:Ca2+/calmodulin system: participation in the progesterone-induced facilitation of lordosis behavior in the ovariectomized estrogen-primed rat. 874 2

Various photoactive phenothiazines were synthesized that possessed a 2-azido, 3-azido, 2-benzoyl, or 1,3,4-trifluoro-2-azido functionality in combination with various modifications of the N-alkyl side chain. These phenothiazines were evaluated for their ability to inhibit the calmodulin-mediated activation of phosphodiesterase (PDE). All were active in inhibiting the action of calmodulin (CaM), but those possessing either a 3-azido and a 4-(4-methyl-1-piperazinyl)butyl side chain or a 2-benzoyl group and 3-(dimethylamino)propyl side chain proved to be most active (I50 = 14 +/- 3 microM and 7 +/- 1 microM, respectively) when compared to the known inhibitor, chlorpromazine (CPZ, I50 = 30 microM). Calmodulin was photolabeled with ca. 35% efficiency in a light- and calcium-dependent fashion using a radiolabeled analog, 3-azido-10-(4-(4-[14C]methyl-1-piperazinyl)butyl)phenothiazine, of one of these compounds. Competition studies using this radiolabeled analog and CPZ were consistent with binding to one or both of the hydrophobic binding pockets of CaM.
 ...
PMID:Synthesis, binding affinity, and cross-linking of monodentate photoactive phenothiazines to calmodulin. 897 53

Calmodulin-like protein has been established as the primary receptor for calcium in eukaryotic as well as prokaryotic cells. The calmodulin-calcium complex regulates a variety of enzymes including nucleotide phosphodiesterase. Recently, the presence of this protein in Mycobacterium leprae has been demonstrated and the effects of phenothiazine-type calmodulin antagonists on in vitro growth of M. leprae in a cell-free culture system were investigated. Two biochemical parameters were used to measure metabolic activity and growth of the organism. Among the six phenothiazine derivatives tested, trifluoperazine appeared to be the most potent in inhibiting the in vitro growth of M. leprae, with an MIC of 10 micrograms/ml. Chlorpromazine, triflupromazine and thioridazine were less active than trifluoperazine, with an MIC of 20 micrograms/ml each, while the other two, acetopromazine and fluphenazine, were totally ineffective even at 80 micrograms/ml. All four compounds inhibited the uptake of labelled acetate, glycine and thymidine by whole cells of M. leprae. This suggests that these phenothiazine derivatives have multiple sites of action and probably affect the synthesis of lipids, proteins and DNA.
 ...
PMID:In vitro activities of phenothiazine-type calmodulin antagonists against Mycobacterium leprae. 1062 9

Two new xanthones identified as 15-chlorotajixanthone hydrate (1) and 14-methoxytajixanthone (2) were isolated from an Emericella sp. strain 25379 along with shamixanthone (3) and tajixanthone hydrate (4). The stereostructures of 1 and 2 were elucidated by spectroscopic and molecular modeling methods. The absolute configuration at the stereogenic centers of 1 was established according to CD measurements. In the case of 2, however, the absolute configuration at C-20 and C-25 was designated as S and R, respectively, by Mosher ester methodology. Thereafter, the configuration at C-14 and C-15 of 2 was established as S and S, respectively by comparing the optical rotation and (1)H-(1)H coupling constant experimental values with those obtained through molecular modeling calculations at DFT B3LYP/DGDZVP level of theory for diasteroisomers 2a-2d. The activation of the calmodulin-sensitive cAMP phosphodiesterase (PDE1) was inhibited in the presence of 1-4 in a concentration-dependent manner. The effect of compounds 2 (IC(50)=5.54 microM) and 4 (IC(50)=5.62 microM) was comparable with that of chlorpromazine (CPZ; IC(50)=7.26 microM), a well known CaM inhibitor used as a positive control. The inhibition mechanism of both compounds was competitive with respect to CaM according to a kinetic study. A docking analysis with 2 and 4 using the AutoDock 4.0 program revealed that they interacted with CaM in the same pocket as trifluoropiperazine (TFP).
 ...
PMID:Calmodulin inhibitors from the fungus Emericella sp. 1901 22

CNP::EGFP transgenic mice, genetically engineered to express the enhanced green fluorescent protein (EGFP) under the control of the 2-3-cyclic nucleotide 3-phosphodiesterase (CNPase) promoter in oligodendroglial and Schwann cells, constitute a very important and widely used tool for the study of oligodendrocyte (OLG) development and function in young mice. Our results showed that CNP::EGFP mice were significantly more susceptible to CPZ-induced demyelination, as evaluated by MBP immunostaining, oligodendroglial progenitor cell (OPC) recruitment and astroglial, microglial and nestin response. This enhanced vulnerability was a consequence of their hypomyelination. CNP::EGFP control mice also displayed a significant decrease in corpus callosum (CC) thickness and MBP immunoreactivity. Morphometric analysis further showed a significant decrease in the frequency of myelinated axons, myelin turns (lamellae) and g-ratio carried out in the optic nerve (ON) and CC of CNP::EGFP, as compared to WT mice. Moreover, our results showed a decrease in the number of axons of small caliber, concomitantly with an increase in the number of axons of bigger size with more and enlarged mitochondria, which suggests a high energy demand. These findings and those displaying that MBP+ cells and NF200 staining in the CNP::EGFP cortex were more sparsely distributed provide evidence of axonal loss, which was supported by a decreased number of NeuN+ cells in the CA3 fields of the hippocampus. Transgenic mice also showed an increase in microglial and astroglial activation, accompanied by enhanced lipid peroxidation and recruitment of morphologically altered OPC. Finally, CNPase protein levels proved to be lower than MBP in the CC, which might indicate an altered pattern in myelin proteins with a CNPase deficiency. Behavioral analysis of adult CNP::EGFP transgenic mice supported our results, as it revealed a decrease in locomotion, exploratory activity and motor impairment, as compared to their WT littermates. Our data highlight the relevance of confronting results obtained in adult CNP::EGFP mice with those observed in WT mice. According to our findings, CNP::EGFP hypomyelination might be triggered by the cellular stress induced by the high level of EGFP expression in mature OLG. Adult CNP::EGFP mice could be considered a useful tool to evaluate future therapies for demyelinating diseases such as multiple sclerosis (MS), since these animals present chronic demyelination with axonal degeneration, a characteristic of such pathologies.
 ...
PMID:Adult CNP::EGFP transgenic mouse shows pronounced hypomyelination and an increased vulnerability to cuprizone-induced demyelination. 2215 18


<< Previous 1 2