Publications by authors named "Juha Juntunen"

7 Publications

  • Page 1 of 1

Modeling of flux through silicone membranes from water.

Eur J Pharm Sci 2008 Aug 5;34(4-5):321-32. Epub 2008 Jun 5.

Department of Medicinal Chemistry, University of Florida, P.O. Box 100485, Gainesville, FL 32610, USA.

Do the Roberts-Sloan (RS) or modified Kasting-Smith-Cooper (KSC) equations that provide good fit to data for maximum flux, from water through mouse or human skin also provide a good fit to data for maximum fluxes through silicone membranes (polydimethylsiloxane, PDMS). The maximum fluxes through silicone membranes from water (J(MPAQ)), molecular weights (MW), solubilities in isopropyl myristate (S(IPM)) and water (S(AQ)) of 31 prodrugs and one parent drug have been fitted to the RS equation, which includes a parameter for dependence on S(AQ), and the KSC equation, which does not, to determine which equation gave the better fit. In addition, the J(MPAQ), MW, S(AQ) and solubilities in octanol (S(OCT)) of 26 diverse molecules from other laboratories were collected and fitted to the RS and KSC equations to determine if the choice of lipid parameter (S(IPM) or S(OCT)) had an effect on which equation gave the better fit. RS gave the better fit to the present prodrug database where: logJ(MPAQ)=-2.454+0.716 logS(IPM)+0.284 logS(AQ)+0.00208 MW, r(2)=0.77. RS also gave the better fit to the database from other laboratories where: logJ(MPAQ)=-2.046+0.667 logS(OCT)+0.333 logS(AQ)-0.00374 MW, r(2)=0.878 after four obvious outliers were removed to give n=22. Thus, data for J(MPAQ) can be fitted to the RS equation, which also provides the best fit to maximum flux from water through mouse or human skin and includes a dependence on S(AQ).
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http://dx.doi.org/10.1016/j.ejps.2008.05.008DOI Listing
August 2008

The effect of water solubility of solutes on their flux through human skin in vitro: a prodrug database integrated into the extended Flynn database.

Int J Pharm 2008 Mar 29;351(1-2):92-103. Epub 2007 Sep 29.

Department of Medicinal Chemistry, University of Florida, PO Box 100485, Gainesville, FL 32610, United States.

A database (n=50) consisting of values of solubility in water, S AQ, solubility in octanol, S OCT, molecular weight, MW, and maximum flux based on the delivery of total species containing a parent drug by its prodrugs through human skin in vitro from water has been integrated into the extended Flynn database (n=114). In addition, data for two more recent contributions (n=8) and one (n=7) contribution that was overlooked for inclusion in the extended Flynn database were added to the prodrug database, as well as the data for the parent drugs (n=6), to give n=71 and n=185 for the total integrated database. This integrated database was fit to five equations where the independent variable was S AQ, S OCT or MW alone or were combinations of S OCT and MW (Kasting-Smith-Cooper, KSC model) or S OCT, S AQ and MW (Roberts-Sloan, RS model). The RS equation gave the best fit: log J MAQ=-2.506+0.538 log S OCT+0.462 log S AQ-0.00402MW, r2=0.839, S.D.=0.423 and the residual (Delta log J MAQ) was 0.474 log units. Integration of a substantial number of prodrugs into the extended Flynn database did not change the dependence of J MAQ on a balance of S AQ and S OCT. No trend in the effect of the prodrug being more or less water soluble than its parent drug on over- or underpredicting flux (+/-Delta'log J MAQ) by the RS model was found. Thus optimization of the S AQ of a prodrug in its design, as well as the design of new drugs, is indicated.
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http://dx.doi.org/10.1016/j.ijpharm.2007.09.034DOI Listing
March 2008

An introduction of a pyridine group into the structure of prolyl oligopeptidase inhibitors.

Bioorg Med Chem Lett 2006 Nov 17;16(21):5590-3. Epub 2006 Aug 17.

Department of Pharmaceutical Chemistry, University of Kuopio, PO Box 1627, FI-70211 Kuopio, Finland.

A series of ionizable prolyl oligopeptidase inhibitors were developed through the introduction of a pyridyl group to the P3 position of the prolyl oligopeptidase inhibitor structure. The study was performed on previously developed prolyl oligopeptidase inhibitors with proline mimetics at the P2 position. The 3-pyridyl group resulted in equipotent compounds as compared to the parent compounds. It was shown that the pyridyl group improves water solubility and, in combination with a 5(R)-tert-butyl-l-prolyl group at the P2 position, good lipophilicity can be achieved.
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http://dx.doi.org/10.1016/j.bmcl.2006.08.029DOI Listing
November 2006

In-vitro corneal permeation of cannabinoids and their water-soluble phosphate ester prodrugs.

J Pharm Pharmacol 2005 Sep;57(9):1153-7

Department of Pharmaceutical Chemistry, University of Kuopio, PO Box 1627, FIN-70211 Kuopio, Finland.

Topically administered cannabinoids have been shown to reduce intraocular pressure by interacting with the ocular cannabinoid receptor. Most cannabinoids have very poor aqueous solubility, which limits their pharmaceutical development and usefulness. In this study, permeation of three cannabinoids (arachidonylethanolamide, R-methanandamide and noladin ether) and their water-soluble phosphate ester prodrugs across isolated rabbit cornea was investigated in vitro. Hydroxypropyl-beta-cyclodextrin (HP-beta-CD) was used to solubilize the parent cannabinoids in permeation studies to achieve the required concentration in donor and receiving cells. Highest fluxes were obtained with lipophilic parent compounds administered with HP-beta-CD, and the fluxes of phosphate esters were 45-70% that of their corresponding parent compounds. Phosphate esters hydrolysed on the surface of the cornea or during the permeation to release the lipophilic parent compound, which further permeated the cornea. No phosphate esters were detected on the endothelial side of the cornea. Although the phosphate esters had lower fluxes than their corresponding parent compounds in these HP-beta-CD formulations, the results are promising and the fluxes of phosphate esters are significantly higher than the fluxes of parent compounds administered as a suspension (due to their low aqueous solubility) without HP-beta-CD.
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http://dx.doi.org/10.1211/jpp.57.9.0009DOI Listing
September 2005

Synthesis, in vitro evaluation, and intraocular pressure effects of water-soluble prodrugs of endocannabinoid noladin ether.

J Med Chem 2003 Nov;46(23):5083-6

Department of Pharmaceutical Chemistry, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland.

The poor aqueous solubility of 2-arachidonyl glyceryl ether (noladin ether) 2 hinders both pharmacological studies and pharmaceutical development. The synthesized mono- and diphosphate esters of noladin ether (4 and 6) considerably increased the aqueous solubility of noladin ether (>40000-fold), showed high stability against chemical hydrolysis in buffer solutions, and were rapidly converted to the parent drug via enzymatic hydrolysis. The monophosphate ester of noladin ether reduced intraocular pressure in normotensive rabbits.
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http://dx.doi.org/10.1021/jm030877jDOI Listing
November 2003

Inhibition of C6 glioma cell proliferation by anandamide, 1-arachidonoylglycerol, and by a water soluble phosphate ester of anandamide: variability in response and involvement of arachidonic acid.

Biochem Pharmacol 2003 Sep;66(5):757-67

Department of Pharmacology and Clinical Neuroscience, Umeå University, SE-90187 Umeå, Sweden.

It has previously been shown that the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG) inhibit the proliferation of C6 glioma cells in a manner that can be prevented by a combination of capsazepine (Caps) and cannabinoid (CB) receptor antagonists. It is not clear whether the effect of 2-AG is due to the compound itself, due to the rearrangement to form 1-arachidonoylglycerol (1-AG) or due to a metabolite. Here, it was found that the effects of 2-AG can be mimicked with 1-AG, both in terms of its potency and sensitivity to antagonism by Caps and CB receptor antagonists. In order to determine whether the effect of Caps could be ascribed to actions upon vanilloid receptors, the effect of a more selective vanilloid receptor antagonist, SB366791 was investigated. This compound inhibited capsaicin-induced Ca(2+) influx into rVR1-HEK293 cells with a pK(B) value of 6.8+/-0.3. The combination of SB366791 and CB receptor antagonists reduced the antiproliferative effect of 1-AG, confirming a vanilloid receptor component in its action. 1-AG, however, showed no direct effect on Ca(2+) influx into rVR1-HEK293 cells indicative of an indirect effect upon vanilloid receptors. Identification of the mechanism involved was hampered by a large inter-experimental variation in the sensitivity of the cells to the antiproliferative effects of 1-AG. A variation was also seen with anandamide, which was not a solubility issue, since its water soluble phosphate ester showed the same variability. In contrast, the sensitivity to methanandamide, which was not sensitive to antagonism by the combination of Caps and CB receptor antagonists, but has similar physicochemical properties to anandamide, did not vary between experiments. This variation greatly reduces the utility of these cells as a model system for the study of the antiproliferative effects of anandamide. Nevertheless, it was possible to conclude that the antiproliferative effects of anandamide were not solely mediated by either its hydrolysis to produce arachidonic acid or its CB receptor-mediated activation of phospholipase A(2) since palmitoyltrifluoromethyl ketone did not prevent the response to anandamide. The same result was seen with the fatty acid amide hydrolase inhibitor palmitoylethylamide. Increasing intracellular arachidonic acid by administration of arachidonic acid methyl ester did not affect cell proliferation, and the modest antiproliferative effect of umbelliferyl arachidonate was not prevented by a combination of Caps and CB receptor antagonists.
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http://dx.doi.org/10.1016/s0006-2952(03)00392-7DOI Listing
September 2003

Anandamide prodrugs. 1. Water-soluble phosphate esters of arachidonylethanolamide and R-methanandamide.

Eur J Pharm Sci 2003 May;19(1):37-43

Department of Pharmaceutical Chemistry, University of Kuopio, PO Box 1627, FIN-70211, Kuopio, Finland

Phosphate esters of arachidonylethanolamide (AEA) and R-methanandamide were synthesized and evaluated as water-soluble prodrugs. Various physicochemical properties (pK(a), partition coefficient, aqueous solubility) were determined for the synthesized phosphate esters. The chemical stability of phosphate esters was determined at pH 7.4. In vitro enzymatic hydrolysis rates were determined in 10% liver homogenate, and in a pure enzyme-containing (alkaline phosphatase) solution at pH 7.4. The intraocular pressure (IOP) lowering properties of R-methanandamide phosphate ester were tested on normotensive rabbits. The phosphate promoiety increased the aqueous solubility of the parent compounds by more than 16500-fold at pH 7.4. Phosphate esters were stable in buffer solutions, but rapidly hydrolyzed to their parent compounds in alkaline phosphatase solution (t(1/2)<<15 s) and liver homogenate (t(1/2)=8-9 min). The phosphate ester of R-methanandamide reduced IOP in rabbits. These results indicate that the phosphate esters of AEA and R-methanandamide are useful water-soluble prodrugs.
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http://dx.doi.org/10.1016/s0928-0987(03)00044-7DOI Listing
May 2003
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