Publications by authors named "Krista Laine"

22 Publications

  • Page 1 of 1

Structural properties for selective and efficient l-type amino acid transporter 1 (LAT1) mediated cellular uptake.

Int J Pharm 2018 Jun 15;544(1):91-99. Epub 2018 Apr 15.

School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.

l-Type amino acid transporter 1 (LAT1) is a sodium-independent exchanger transporting large neural amino acids and several amino-acid mimicking drugs across the cell membranes. LAT1 is highly expressed at the blood brain barrier (BBB) and in numerous cancer cells and is therefore a potential drug target. However, structural features affecting the ability to bind to LAT1 and the cellular translocation by LAT1 are unclear. In the present study we determined the binding to and transport through human LAT1 of several compounds into the human breast adenocarcinoma cells (MCF-7). We show that the meta-conjugation of l-phenylalanine increases binding to human LAT1 compared to para-conjugation or aliphatic amino acid moiety. Furthermore, large, rigid and aromatic meta-substituted l-phenylalanine derivative enabled selective and efficient LAT1-mediated cellular uptake. Our results also demonstrates that in addition to binding studies, it is of utmost importance to determine the cellular accumulation of compounds. It provides crucial information on transport efficiency and selectivity of transport mechanisms that the compounds are able to utilize. Overall, these structural findings and the methodology used herein are exploitable to design LAT1-utilizing compounds, such as markers for cancer imaging and drug molecules, enabling more effective and safer treatments for cancer in the future.
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http://dx.doi.org/10.1016/j.ijpharm.2018.04.025DOI Listing
June 2018

Quantitative insight into the design of compounds recognized by the L-type amino acid transporter 1 (LAT1).

ChemMedChem 2014 Dec 9;9(12):2699-707. Epub 2014 Sep 9.

School of Pharmacy, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio (Finland).

L-Type amino acid transporter 1 (LAT1) is a transmembrane protein expressed abundantly at the blood-brain barrier (BBB), where it ensures the transport of hydrophobic acids from the blood to the brain. Due to its unique substrate specificity and high expression at the BBB, LAT1 is an intriguing target for carrier-mediated transport of drugs into the brain. In this study, a comparative molecular field analysis (CoMFA) model with considerable statistical quality (Q(2) =0.53, R(2) =0.75, Q(2) SE=0.77, R(2) SE=0.57) and good external predictivity (CCC=0.91) was generated. The model was used to guide the synthesis of eight new prodrugs whose affinity for LAT1 was tested by using an in situ rat brain perfusion technique. This resulted in the creation of a novel LAT1 prodrug with L-tryptophan as the promoiety; it also provided a better understanding of the molecular features of LAT1-targeted high-affinity prodrugs, as well as their promoiety and parent drug. The results obtained will be beneficial in the rational design of novel LAT1-binding prodrugs and other compounds that bind to LAT1.
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http://dx.doi.org/10.1002/cmdc.201402281DOI Listing
December 2014

Design, synthesis and brain uptake of LAT1-targeted amino acid prodrugs of dopamine.

Pharm Res 2013 Oct;30(10):2523-37

School of Pharmacy, University of Eastern Finland, Kuopio, Finland.

Purpose: Drug delivery to the brain is impeded by the blood-brain barrier (BBB). Here, we attempted to enhance the brain uptake of cationic dopamine by utilizing the large amino acid transporter 1 (LAT1) at the BBB by prodrug approach.

Methods: Three amino acid prodrugs of dopamine were synthesized and their prodrug properties were examined in vitro. Their LAT1-binding and BBB-permeation were studied using the in situ rat brain perfusion technique. The brain uptake after intravenous administration and the dopamine-releasing ability in the rat striatum after intraperitoneal administration were also determined for the most promising prodrug.

Results: All prodrugs underwent adequate cleavage in rat tissue homogenates. The prodrug with phenylalanine derivative as the promoiety had both higher affinity for LAT1 and better brain uptake properties than those with an alkyl amino acid - mimicking promoiety. The phenylalanine prodrug was taken up into the brain after intravenous injection but after intraperitoneal injection the prodrug did not elevate striatal dopamine concentrations above those achieved by corresponding L-dopa treatment.

Conclusions: These results indicate that attachment of phenylalanine to a cationic drug via an amide bond from the meta-position of its aromatic ring could be highly applicable in prodrug design for LAT1-mediated CNS-delivery of not only anionic but also cationic polar drugs.
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http://dx.doi.org/10.1007/s11095-012-0966-3DOI Listing
October 2013

Convenient microwave-assisted synthesis of lipophilic sulfenamide prodrugs of metformin.

Eur J Pharm Sci 2013 Jul 1;49(4):624-8. Epub 2013 Jun 1.

School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland.

A convenient microwave-assisted synthesis of lipophilic sulfenamide prodrugs of antidiabetic agent, metformin, is reported in this study. These acyclic prodrugs were synthesized directly from selected disulfides with basic metformin and silver nitrate by a one-pot reaction under microwave irradiation. The prepared prodrugs had significantly increased lipophilicity, which resulted in excellent permeability of the octylthio prodrug of metformin across a Caco-2 cell monolayer. According to our preliminary in vivo studies, the octylthio prodrug was also absorbed mostly intact after oral administration in rats. In conclusion, this study shows that these types of more lipophilic sulfenamide prodrugs can be promising candidates to improve permeability and passive absorption of highly water-soluble metformin.
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http://dx.doi.org/10.1016/j.ejps.2013.05.023DOI Listing
July 2013

Structure-activity relationship study of compounds binding to large amino acid transporter 1 (LAT1) based on pharmacophore modeling and in situ rat brain perfusion.

Eur J Pharm Sci 2013 Feb 8;48(3):523-31. Epub 2012 Dec 8.

School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.

Large neutral amino acid transporter 1 (LAT1) is predominantly expressed at the blood-brain barrier and it has a major role in transporting neutral amino acids into the brain. LAT1 has the potential to function as a drug carrier for improved drug brain delivery which makes it an intriguing target protein for central nervous system disorders, e.g., Alzheimer's disease, Parkinson's disease and brain tumors. In this study, a 3D pharmacophore was generated for a set of LAT1 substrates whose binding affinities were studied using competitive inhibition of the brain uptake of [¹⁴C]-L-leucine with an in situ rat brain perfusion method. The pharmacophore highlights the most important molecular features shared by efficient LAT1-binding compounds and elucidates their 3D-arrangement in detail. This clarifies the structure-activity relationships of LAT1 substrates and provides insights for making a binding hypothesis. The results can be further applied in the design of novel efficient LAT1 substrates.
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http://dx.doi.org/10.1016/j.ejps.2012.11.014DOI Listing
February 2013

Amino acids as promoieties in prodrug design and development.

Adv Drug Deliv Rev 2013 Oct 22;65(10):1370-85. Epub 2012 Oct 22.

Bristol-Myers Squibb Company, USA. Electronic address:

Prodrugs are biologically inactive agents that upon biotransformation in vivo result in active drug molecules. Since prodrugs might alter the tissue distribution, efficacy and the toxicity of the parent drug, prodrug design should be considered at the early stages of preclinical development. In this regard, natural and synthetic amino acids offer wide structural diversity and physicochemical properties. This review covers the use of amino acid prodrugs to improve poor solubility, poor permeability, sustained release, intravenous delivery, drug targeting, and metabolic stability of the parent drug. In addition, practical considerations and challenges associated with the development of amino acid prodrugs are also covered.
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http://dx.doi.org/10.1016/j.addr.2012.10.001DOI Listing
October 2013

In vitro and in vivo evaluation of a sulfenamide prodrug of basic metformin.

J Pharm Sci 2012 Aug 30;101(8):2854-60. Epub 2012 May 30.

School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.

In the present study, a previously described sulfenamide prodrug of a basic antidiabetic drug, metformin, was evaluated further. This sulfenamide prodrug was designed to improve the permeability and consequently the oral absorption and bioavailability (F) of the highly water-soluble metformin. Bioactivation of the prodrug was mediated by reduced glutathione, but it has been reported that sulfenamide prodrugs can also be bioactivated by other endogenous thiols like cysteine, and free thiol-containing proteins. Consistent with earlier findings for a sulfenamide prodrug of a weakly acid drug, linezolid, the permeability studies indicated that the metformin prodrug was also prematurely bioactivated on the apical surface of the Caco-2 cell monolayer. Nevertheless, the bioavailability of metformin was increased by approximately 25% after oral administration of the prodrug in rats, most probably because of better oral absorption. This indicates that the sulfenamide prodrug approach may be used to improve the moderate oral bioavailability of metformin, which may help to decrease the uncomfortable gastrointestinal adverse effects associated with metformin therapy as the daily doses of metformin can be reduced. Furthermore, the present study confirms that the applicability of the sulfenamide prodrug approach can be successfully extended from weak NH acids to very basic guanide-type drugs.
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http://dx.doi.org/10.1002/jps.23221DOI Listing
August 2012

Large amino acid transporter 1 (LAT1) prodrugs of valproic acid: new prodrug design ideas for central nervous system delivery.

Mol Pharm 2011 Oct 9;8(5):1857-66. Epub 2011 Aug 9.

School of Pharmacy, University of Eastern Finland, PO Box 1627, FI-70211, Kuopio, Finland.

Central nervous system (CNS) drug delivery is a major challenge in drug development because the blood-brain barrier (BBB) efficiently restricts the entry of drug molecules into the CNS at sufficient amounts. The brain uptake of poorly penetrating drugs could be improved by utilizing the transporters at the BBB with a prodrug approach. In this study, we designed four phenylalanine derivatives of valproic acid and studied their ability to utilize a large amino acid transporter 1 (LAT1) in CNS delivery with an aim to show that the meta-substituted phenylalanine prodrugs bind to LAT1 with a higher affinity compared with the affinity of the para-substituted derivatives. All of the prodrugs crossed the BBB carrier mediatedly via LAT1 in in situ rat brain perfusion. For the first time, we introduced a novel meta-substituted phenylalanine analogue promoiety which improved the LAT1 affinity 10-fold and more importantly the rat brain uptake of the prodrug 2-fold compared with those of the para-substituted derivatives. Therefore, we have characterized a new prodrug design idea for CNS drug delivery utilizing a transporter-mediated prodrug approach.
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http://dx.doi.org/10.1021/mp2001878DOI Listing
October 2011

Brain uptake of ketoprofen-lysine prodrug in rats.

Int J Pharm 2010 Oct 19;399(1-2):121-8. Epub 2010 Aug 19.

School of Pharmacy, University of Eastern Finland, Kuopio, Finland.

The blood-brain barrier (BBB) controls the entry of xenobiotics into the brain. Often the development of central nervous system drugs needs to be terminated because of their poor brain uptake. We describe a way to achieve large neutral amino acid transporter (LAT1)-mediated drug transport into the rat brain. We conjugated ketoprofen to an amino acid l-lysine so that the prodrug could access LAT1. The LAT1-mediated brain uptake of the prodrug was demonstrated with in situ rat brain perfusion technique. The ability of the prodrug to deliver ketoprofen into the site of action, the brain intracellular fluid, was determined combining in vivo and in vitro experiments. A rapid brain uptake from blood and cell uptake was seen both in in situ and in vivo experiments. Therefore, our results show that a prodrug approach can achieve uptake of drugs via LAT1 into the brain intracellular fluid. The distribution of the prodrug in the brain parenchyma and the site of parent drug release in the brain were shown with in vivo and in vitro studies. In addition, our results show that although lysine or ketoprofen are not LAT1-substrates themselves, by combining these molecules, the formed prodrug has affinity for LAT1.
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http://dx.doi.org/10.1016/j.ijpharm.2010.08.019DOI Listing
October 2010

Design, synthesis and in vitro/in vivo evaluation of orally bioavailable prodrugs of a catechol-O-methyltransferase inhibitor.

Bioorg Med Chem Lett 2010 Apr 19;20(8):2614-6. Epub 2010 Feb 19.

University of Eastern Finland, School of Pharmacy, FI-70211 Kuopio, Finland.

Compound 1 is an investigational, nanomolar inhibitor of catechol-O-methyltransferase (COMT) that suffers from poor oral bioavailability, most probably due to its low lipophilicity throughout most of the gastrointestinal tract and, to a lesser extent, its rapid systemic clearance. Several lipophilic esters were designed as prodrugs and synthesized in an attempt to optimize presystemic drug absorption. A modest twofold increase in 6-h exposure of 1 was observed with two prodrugs, compared to that of 1, after oral treatment in rats.
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http://dx.doi.org/10.1016/j.bmcl.2010.02.057DOI Listing
April 2010

The first bioreversible prodrug of metformin with improved lipophilicity and enhanced intestinal absorption.

J Med Chem 2009 Jul;52(14):4142-8

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

Metformin is a potent antidiabetic agent and currently used as a first-line treatment for patients with type 2 diabetes. Unfortunately, the moderate absorption and uncomfortable gastrointestinal adverse effects associated with metformin therapy impair its use. In this study, two novel prodrugs of a biguanidine functionality containing antidiabetic agent, metformin, were designed, synthesized, and evaluated in vitro and in vivo to accomplish improved lipophilicity and, consequently, enhanced oral absorption of this highly water-soluble drug. These results represent that the more lipophilic prodrug 2a biotransformed quantitatively to metformin mainly after absorption. The enhanced oral absorption consequently promoted the bioavailability of metformin from 43% to 65% in rats. Thus, this novel prodrug may offer a solution to reduce the required daily doses of metformin, which may decrease the uncomfortable adverse effects associated with metformin therapy.
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http://dx.doi.org/10.1021/jm900274qDOI Listing
July 2009

Glucose promoiety enables glucose transporter mediated brain uptake of ketoprofen and indomethacin prodrugs in rats.

J Med Chem 2009 May;52(10):3348-53

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

The brain uptake of solutes is efficiently governed by the blood-brain barrier (BBB). The BBB expresses a number of carrier-mediated transport mechanisms, and new knowledge of these BBB transporters can be used in the rational targeted delivery of drug molecules for active transport. One attractive approach is to conjugate an endogenous transporter substrate to the active drug molecule to utilize the prodrug approach. In the present study, ketoprofen and indomethacin were conjugated with glucose and the brain uptake mechanism of the prodrugs was determined with the in situ rat brain perfusion technique. Two of the prodrugs were able to significantly inhibit the uptake of glucose transporter (GluT1)-mediated uptake of glucose, thereby demonstrating affinity to the transporter. Furthermore, the prodrugs were able to cross the BBB in a temperature-dependent manner, suggesting that the brain uptake of the prodrugs is carrier-mediated.
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http://dx.doi.org/10.1021/jm8015409DOI Listing
May 2009

Prodrug approaches for CNS delivery.

AAPS J 2008 5;10(1):92-102. Epub 2008 Feb 5.

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

Central nervous system (CNS) drug delivery remains a major challenge, despite extensive efforts that have been made to develop novel strategies to overcome obstacles. Prodrugs are bioreversible derivatives of drug molecules that must undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which subsequently exerts the desired pharmacological effect. In both drug discovery and drug development, prodrugs have become an established tool for improving physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically active agents that overcome barriers to a drug's usefulness. This review provides insight into various prodrug strategies explored to date for CNS drug delivery, including lipophilic prodrugs, carrier- and receptor-mediated prodrug delivery systems, and gene-directed enzyme prodrug therapy.
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http://dx.doi.org/10.1208/s12248-008-9009-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2751454PMC
September 2008

Large neutral amino acid transporter enables brain drug delivery via prodrugs.

J Med Chem 2008 Feb 25;51(4):932-6. Epub 2008 Jan 25.

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

The blood-brain barrier efficiently controls the entry of drug molecules into the brain. We describe a feasible means to achieve carrier-mediated drug transport into the rat brain via the specific, large neutral amino acid transporter (LAT1) by conjugating a model compound to L-tyrosine. A hydrophilic drug, ketoprofen, that is not a substrate for LAT1 was chosen as a model compound. The mechanism and the kinetics of the brain uptake of the prodrug were determined with an in situ rat brain perfusion technique. The brain uptake of the prodrug was found to be concentration-dependent. In addition, a specific LAT1 inhibitor significantly decreased the brain uptake of the prodrug. Therefore, our results reveal for the first time that a drug-substrate conjugate is able to transport drugs into the brain via LAT1.
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http://dx.doi.org/10.1021/jm701175dDOI Listing
February 2008

Synthesis, hydrolysis, and intraocular pressure lowering effects of fadolmidine prodrugs.

Int J Pharm 2005 May;295(1-2):121-7

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

The objective of this study was to synthesize and evaluate various esters of fadolmidine, a novel alpha2-adrenergic agonist, as potential ophthalmic prodrugs. All studied prodrugs released the parent drug (i.e., fadolmidine) quantitatively via enzymatic hydrolysis in 80% human serum. The pivalyl ester was considered to be the most promising prodrug in this series, due to its good chemical stability (pH 5.0; 37 degrees C; t(1/2)=310 days) and optimal lipophilicity (logP(app)=1.8; 1-octanol/phosphate buffer, pH 5.0), and was selected for further evaluation of its intraocular pressure (IOP) lowering effects in normotensive rabbits. The pivalyl ester showed increased IOP lowering ability when compared to an equimolar dose of fadolmidine, which was probably due to its increased lipophilicity and subsequent enhanced corneal penetration. The duration of action for the pivalyl ester was also longer than that of fadolmidine.
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http://dx.doi.org/10.1016/j.ijpharm.2005.02.002DOI Listing
May 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

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

Topically administered CB(2)-receptor agonist, JWH-133, does not decrease intraocular pressure (IOP) in normotensive rabbits.

Life Sci 2003 Jan;72(7):837-42

Department of Pharmaceutical Chemistry, University of Kuopio, POB 1627, Finland.

Recent IOP and receptor localization studies suggest that the IOP effects of cannabinoids are mediated via ocular CB(1) receptors. However, it is not yet known whether CB(2) receptor agonists decrease IOP. In this study, the IOP-lowering effects of the CB(2) receptor agonist JWH-133 were studied in normotensive rabbits, and compared with CP55,940. JWH-133 and CP55,940 were dissolved in aqueous hydroxypropyl-beta-cyclodextrin (HP-beta-CD) solutions and propylene glycol. The eye drops (25 microl) were administered unilaterally to the rabbit eye, and IOPs were measured at fixed time intervals. JWH-133, dissolved in either HP-beta-CD (doses = 10 microg and 25 microg) or propylene glycol (dose = 62.5 microg), did not have any effect on IOP when compared to vehicle treatments. In contrast, CP55,940 formulated in HP-beta-CD (doses = 25 microg and 62.5 microg) or propylene glycol (dose = 62.5 microg) reduced IOP significantly compared to vehicle treatments. The results suggest that topically administered CB(2) receptor agonist, JWH-133, does not decrease IOP in normotensive rabbits at the doses and formulations used, and thus, CB(2) receptor agonists may not be useful as cannabinoid-based IOP-lowering therapeutics.
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http://dx.doi.org/10.1016/s0024-3205(02)02339-1DOI Listing
January 2003

Comparison of the enzymatic stability and intraocular pressure effects of 2-arachidonylglycerol and noladin ether, a novel putative endocannabinoid.

Invest Ophthalmol Vis Sci 2002 Oct;43(10):3216-22

Departments of Pharmaceutical Chemistry, University of Kuopio, Finland.

Purpose: The endogenous cannabinoids N-arachidonylethanolamide (AEA) and 2-arachidonylglycerol (2-AG) are known to decrease intraocular pressure (IOP). Recently, a novel putative endogenous cannabinoid, noladin ether, was isolated in porcine and rat brains. In the present study, both the degradation of endogenous cannabinoids in ocular tissues and the effect on IOP of 2-AG and noladin ether were compared.

Methods: The rates of enzymatic degradation for AEA, 2-AG, and noladin ether were determined in bovine cornea and iris-ciliary body homogenates. 2-AG and noladin ether were dissolved in either hydroxypropyl-beta-cyclodextrin (HP-beta-CD) or propylene glycol and administered unilaterally to the rabbit eye. IOPs were measured in the treated and untreated eyes. The CB1 receptor antagonist AM251 was administered topically 15 minutes before the cannabinoids to investigate whether CB1 receptors mediate the effect on IOP produced by 2-AG and noladin ether.

Results: Noladin ether degraded more slowly than either 2-AG or AEA in the iris-ciliary body and cornea homogenates. The effect on IOP of 2-AG was biphasic (i.e., an initial increase in IOP followed by a reduction in the treated eye). Noladin ether decreased IOP immediately after topical administration, and no initial IOP increase was observed in the treated eye. The CB1 receptor antagonist AM251 (25 micro g) blocked the effect on IOP of noladin ether but did not affect the action of 2-AG.

Conclusions: Topical administration of the novel putative endogenous cannabinoid noladin ether decreased IOP in rabbits. This IOP reduction was most probably mediated through the CB1 receptor. The effect on IOP of noladin ether differed from those of the known endogenous cannabinoids AEA and 2-AG, probably because of its more stable chemical structure.
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October 2002

Cannabinoids in the treatment of glaucoma.

Pharmacol Ther 2002 Aug;95(2):203-20

Department of Pharmaceutical Chemistry, University of Kuopio, Finland.

The leading cause of irreversible blindness is glaucoma, a disease normally characterized by the development of ocular hypertension and consequent damage to the optic nerve at its point of retinal attachment. This results in a narrowing of the visual field, and eventually results in blindness. A number of drugs are available to lower intraocular pressure (IOP), but, occasionally, they are ineffective or have intolerable side-effects for some patients and can lose efficacy with chronic administration. The smoking of marijuana has decreased IOP in glaucoma patients. Cannabinoid drugs, therefore, are thought to have significant potential for pharmaceutical development. However, as the mechanism surrounding their effect on IOP initially was thought to involve the CNS, issues of psychoactivity hindered progress. The discovery of ocular cannabinoid receptors implied an explanation for the induction of hypotension by topical cannabinoid applications, and has stimulated a new phase of ophthalmic cannabinoid research. Featured within these investigations is the possibility that at least some cannabinoids may ameliorate optic neuronal damage through suppression of N-methyl-D-aspartate receptor hyperexcitability, stimulation of neural microcirculation, and the suppression of both apoptosis and damaging free radical reactions, among other mechanisms. Separation of therapeutic actions from side-effects now seems possible through a diverse array of novel chemical, pharmacological, and formulation strategies.
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http://dx.doi.org/10.1016/s0163-7258(02)00259-0DOI Listing
August 2002

Effect of the enzyme inhibitor, phenylmethylsulfonyl fluoride, on the IOP profiles of topical anandamides.

Invest Ophthalmol Vis Sci 2002 Feb;43(2):393-7

Department of Pharmaceutical Chemistry, University of Kuopio, Kuopio, Finland.

Purpose: Earlier studies have suggested that the intraocular pressure (IOP) effects of topical arachidonylethanolamide (AEA) are mediated through its fatty acid metabolite, rather than through AEA, per se. The purpose of this study was to investigate whether the topical anandamides AEA and arachidonyl propionitrileamide (APN) decrease IOP when their enzymatic degradation is prevented by phenylmethylsulfonyl fluoride (PMSF) and whether the neuronal cannabinoid (CB1) receptor mediates the IOP responses of an undegraded AEA, through the use of its specific antagonist SR141716A.

Methods: AEA or APN were each formulated in aqueous 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) solutions and administered unilaterally to the rabbit eye (dose, 62.5 microg per rabbit). To prevent the degradation of AEA or APN, the rabbits were pretreated with a subcutaneous (SC) PMSF injection (0.22-22 mg/kg) 30 minutes before eye drop instillation. To determine whether the neuronal cannabinoid (CB1) receptor mediates the hypotensive IOP effects of undegraded AEA, the rabbits were pretreated with simultaneous SC injections of a CB1 receptor antagonist SR141716A (1.2-2.1 mg/kg) and PMSF (2.2 mg/kg) before the ocularly applied AEA.

Results: In the absence of PMSF, the IOP profiles of AEA and APN showed a biphasic ocular effect--that is, an initial increase of IOP followed by IOP hypotension in the treated eye. In the presence of PMSF (2.2 mg/kg for AEA and 22 mg/kg for APN), IOP profiles showed immediate IOP reduction in the treated eye. SR141716A antagonized the IOP reduction caused by the undegraded AEA.

Conclusions: These results indicate that the apparently undegraded AEA and APN decrease IOP in normotensive rabbits. AEA-induced IOP reduction in the presence of PMSF is probably mediated through a CB1 receptor.
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February 2002
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