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Dive into the research topics where Teija Parkkari is active.

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Featured researches published by Teija Parkkari.


Biophysical Journal | 2010

Electrostatic Tuning of Cellular Excitability

Sara I. Börjesson; Teija Parkkari; Sven Hammarström; Fredrik Elinder

Voltage-gated ion channels regulate the electric activity of excitable tissues, such as the heart and brain. Therefore, treatment for conditions of disturbed excitability is often based on drugs that target ion channels. In this study of a voltage-gated K channel, we propose what we believe to be a novel pharmacological mechanism for how to regulate channel activity. Charged lipophilic substances can tune channel opening, and consequently excitability, by an electrostatic interaction with the channels voltage sensors. The direction of the effect depends on the charge of the substance. This was shown by three compounds sharing an arachidonyl backbone but bearing different charge: arachidonic acid, methyl arachidonate, and arachidonyl amine. Computer simulations of membrane excitability showed that small changes in the voltage dependence of Na and K channels have prominent impact on excitability and the tendency for repetitive firing. For instance, a shift in the voltage dependence of a K channel with -5 or +5 mV corresponds to a threefold increase or decrease in K channel density, respectively. We suggest that electrostatic tuning of ion channel activity constitutes a novel and powerful pharmacological approach with which to affect cellular excitability.


Proceedings of the National Academy of Sciences of the United States of America | 2015

Polyunsaturated fatty acid analogs act antiarrhythmically on the cardiac IKs channel

Sara I. Liin; Malin Silverå Ejneby; Rene Barro-Soria; Mark A. Skarsfeldt; Johan E. Larsson; Frida Starck Härlin; Teija Parkkari; Bo Hjorth Bentzen; Nicole Schmitt; H. Peter Larsson; Fredrik Elinder

Significance More than 300 mutations in the genes encoding the cardiac IKs channel have been identified in patients with cardiac arrhythmia. These mutations cause either loss of function or gain of function of the IKs channel. This study describes how polyunsaturated fatty acids and their analogues activate or inhibit the IKs channel. These modulators can restore rhythmic firing in arrhythmic firing cardiac myocytes and restore prolonged QT interval in guinea pig hearts. The study also describes a mechanism by which an auxiliary β-subunit alters the pharmacological sensitivity of the IKs channel. Our findings may form the basis for future design of antiarrhythmic compounds that target IKs channels for treating different cardiac arrhythmias caused by mutations in the IKs channel. Polyunsaturated fatty acids (PUFAs) affect cardiac excitability. Kv7.1 and the β-subunit KCNE1 form the cardiac IKs channel that is central for cardiac repolarization. In this study, we explore the prospects of PUFAs as IKs channel modulators. We report that PUFAs open Kv7.1 via an electrostatic mechanism. Both the polyunsaturated acyl tail and the negatively charged carboxyl head group are required for PUFAs to open Kv7.1. We further show that KCNE1 coexpression abolishes the PUFA effect on Kv7.1 by promoting PUFA protonation. PUFA analogs with a decreased pKa value, to preserve their negative charge at neutral pH, restore the sensitivity to open IKs channels. PUFA analogs with a positively charged head group inhibit IKs channels. These different PUFA analogs could be developed into drugs to treat cardiac arrhythmias. In support of this possibility, we show that PUFA analogs act antiarrhythmically in embryonic rat cardiomyocytes and in isolated perfused hearts from guinea pig.


Journal of Medicinal Chemistry | 2013

Chiral 1,3,4-Oxadiazol-2-ones as Highly Selective FAAH Inhibitors

Jayendra Z. Patel; Teija Parkkari; Tuomo Laitinen; Agnieszka A. Kaczor; Susanna M. Saario; Juha R. Savinainen; Dina Navia-Padanius; Mariateresa Cipriano; Jukka Leppänen; Igor O. Koshevoy; Antti Poso; Christopher J. Fowler; Jarmo T. Laitinen; Tapio Nevalainen

In the present study, identification of chiral 1,3,4-oxadiazol-2-ones as potent and selective FAAH inhibitors has been described. The separated enantiomers showed clear differences in the potency and selectivity toward both FAAH and MAGL. Additionally, the importance of the chirality on the inhibitory activity and selectivity was proven by the simplification approach by removing a methyl group at the 3-position of the 1,3,4-oxadiazol-2-one ring. The most potent compound of the series, the S-enantiomer of 3-(1-(4-isobutylphenyl)ethyl)-5-methoxy-1,3,4-oxadiazol-2(3H)-one (JZP-327A, 51), inhibited human recombinant FAAH (hrFAAH) in the low nanomolar range (IC50 = 11 nM), whereas its corresponding R-enantiomer 52 showed only moderate inhibition toward hrFAAH (IC50 = 0.24 μM). In contrast to hrFAAH, R-enantiomer 52 was more potent in inhibiting the activity of hrMAGL compared to S-enantiomer 51 (IC50 = 4.0 μM and 16% inhibition at 10 μM, respectively). The FAAH selectivity of the compound 51 over the supposed main off-targets, MAGL and COX, was found to be >900-fold. In addition, activity-based protein profiling (ABPP) indicated high selectivity over other serine hydrolases. Finally, the selected S-enantiomers 51, 53, and 55 were shown to be tight binding, slowly reversible inhibitors of the hrFAAH.


European Journal of Medicinal Chemistry | 2015

New quinolone- and 1,8-naphthyridine-3-carboxamides as selective CB2 receptor agonists with anticancer and immuno-modulatory activity.

Clementina Manera; Anna Maria Malfitano; Teija Parkkari; Valentina Lucchesi; Sara Carpi; Stefano Fogli; Simone Bertini; Chiara Laezza; Alessia Ligresti; Giuseppe Saccomanni; Juha R. Savinainen; Elena Ciaglia; Simona Pisanti; Patrizia Gazzerro; Vincenzo Di Marzo; Paola Nieri; Marco Macchia; Maurizio Bifulco

Several recent studies suggest that selective CB2 receptor agonists may represent a valid pharmacological approach in the treatment of various diseases due to the absence of relevant psychoactive side effect. In this study, we synthesized and tested a series of new quinoline-2(1H)-one- and 4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine derivatives characterized by a 4-methylcyclohexylamido substituent in position 3 of the heterocyclic nucleus with high CB2 receptor affinity and selectivity. Two compounds showing the best binding and selectivity profile behaved as a full agonist and a partial agonist at the CB2 receptor and induced a concentration-dependent decrease of cell viability on LNCaP, a prostatic cancer cell line expressing CB2 receptor. Moreover considering that the CB2 receptor is mainly expressed in cells and organs of the immune system, the same compounds were studied for their potential immune-modulatory and anti-inflammatory effects in activated lymphocytes isolated from healthy controls and multiple sclerosis (MS) patients.


European Journal of Pharmaceutical Sciences | 2015

Synthesis, in vitro and in vivo evaluation of 1,3,5-triazines as cannabinoid CB2 receptor agonists.

Sari Yrjölä; Mirkka Sarparanta; Anu J. Airaksinen; Maria Hytti; Anu Kauppinen; Sanna Pasonen-Seppänen; Barbara Adinolfi; Paola Nieri; Clementina Manera; Outi Keinänen; Antti Poso; Tapio Nevalainen; Teija Parkkari

The cannabinoid receptors type 2 (CBR2) are attractive therapeutic targets of the endocannabinoid signaling system (ECS) as they are not displaying the undesired psychotropic and cardiovascular side-effects seen with cannabinoid receptor type 1 (CB1R) agonists. In continuation of our previous work on 2,4,6-trisubstituted 1,3,5-triazines as potent CB2 agonists, we synthesized an additional series of more polar analogues (1-10), which were found to possess high CB2R agonist activity with enhanced water solubility. The most potent compound in the series was N-(adamantan-1-yl)-4-ethoxy-6-(4-(2-fluoroethyl)piperazin-1-yl)-1,3,5-triazin-2-amine (9) with EC50 value of 0.60nM. To further evaluate the biological effects of the compounds, the selected compounds were tested in vitro against four different cell lines. A human retinal pigment epithelial cell line (ARPE-19) was used to evaluate the cytotoxicity of the compounds whereas an androgen-sensitive human prostate adenocarcinoma cell line (LNCaP), a Jurkat leukemia cell line and a C8161 melanoma cell line were used to assess the antiproliferative activity of the compounds. The most interesting results were obtained for N-(adamantan-1-yl)-4-ethoxy-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (6), which induced cell viability decrease in prostate and leukemia cell lines, and diminished proliferation of C8161 melanoma cells. The results could be reversed in leukemia cells with the selective CB2R antagonist AM630, whereas in prostate cells the AM630 induced a significant cell viability decrease with a mechanism probably unlinked to CB2 cannabinoid receptor. The antiproliferative effect of 6 on the melanoma cells seemed not to be mediated via the CB1R or CB2R. No cytotoxicity was detected against ARPE-19 cell line at concentrations of 1 and 10μM for compound 6. However, at 30μM concentration the compound 6 decreased the cell viability. Finally, in order to estimate in vivo behavior of these compounds, (18)F labeled PET ligand, N-cyclopentyl-4-ethoxy-6-(4-(2-fluoro-18-ethyl)piperazin-1-yl)-1,3,5-triazin-2-amine ([(18)F]5), was synthesized and its biodistribution was determined in healthy male Sprague-Dawley rats. As a result, the tracer showed a rapid (<15min) elimination in urine accompanied by a slower excretion via the hepatobiliary route. In conclusion, we further demonstrated that 1,3,5-triazine scaffold serves as a suitable template for the design of highly potent CB2R agonists with reasonable water solubility properties. The compounds may be useful when studying the role of the endocannabinoid system in different diseases. The triazine scaffold is also a promising candidate for the development of new CB2R PET ligands.


Molecular Pharmacology | 2014

Robust hydrolysis of prostaglandin glycerol esters by human monoacylglycerol lipase (MAGL).

Savinainen; Emilia Kansanen; Tatu Pantsar; Dina Navia-Paldanius; Teija Parkkari; Marko Lehtonen; Tuomo Laitinen; Tapio Nevalainen; Antti Poso; Anna-Liisa Levonen; Jarmo T. Laitinen

The primary route of inactivation of the endocannabinoid 2-arachidonoylglycerol in the central nervous system is through enzymatic hydrolysis, mainly carried out by monoacylglycerol lipase (MAGL), along with a small contribution by the α/β-hydrolase domain (ABHD) proteins ABHD6 and ABHD12. Recent methodological progress allowing kinetic monitoring of glycerol liberation has facilitated substrate profiling of the human endocannabinoid hydrolases, and these studies have revealed that the three enzymes have distinct monoacylglycerol substrate and isomer preferences. Here, we have extended this substrate profiling to cover four prostaglandin glycerol esters, namely, 15-deoxy-Δ12,14-prostaglandin J2-2-glycerol (15d-PGJ2-G), PGD2-G, PGE2-G, and PGF2α-G. We found that the three enzymes hydrolyzed the tested substrates, albeit with distinct rates and preferences. Although human ABHD12 (hABHD12) showed only marginal activity toward PGE2-G, hABHD6 preferentially hydrolyzed PGD2-G, and human MAGL (hMAGL) robustly hydrolyzed all four. This was particularly intriguing for MAGL activity toward 15d-PGJ2-G whose hydrolysis rate rivaled that of the best monoacylglycerol substrates. Molecular modeling studies combined with kinetic analysis supported favorable interaction with the hMAGL active site. Long and short MAGL isoforms shared a similar substrate profile, and hMAGL hydrolyzed 15d-PGJ2-G also in living cells. The ability of 15d-PGJ2-G to activate the canonical nuclear factor erythroid 2-related factor (Nrf2) signaling pathway used by 15d-PGJ2 was assessed, and these studies revealed for the first time that 15d-PGJ2 and 15d-PGJ2-G similarly activated Nrf2 signaling as well as transcription of target genes of this pathway. Our study challenges previous claims regarding the ability of MAGL to catalyze PG-G hydrolysis and extend the MAGL substrate profile beyond the classic monoacylglycerols.


Molecular Pharmacology | 2014

Mutation of Cys242 of Human Monoacylglycerol Lipase Disrupts Balanced Hydrolysis of 1- and 2-Monoacylglycerols and Selectively Impairs Inhibitor Potency

Tuomo Laitinen; Dina Navia-Paldanius; Roosa Rytilahti; Joona J. T. Marjamaa; Julie Kařízková; Teija Parkkari; Tatu Pantsar; Antti Poso; Jarmo T. Laitinen; Juha R. Savinainen

Considerable progress has been made in recent years in developing selective, potent monoacylglycerol lipase (MAGL) inhibitors. In the investigations of measures to inhibit this enzyme, less attention has been paid to improving our understanding of its catalytic mechanisms or substrate preferences. In our study, we used site-directed mutagenesis, and we show via versatile activity assays combined with molecular modeling that Cys242 and Tyr194, the two opposing amino acid residues in the catalytic cavity of MAGL, play important roles in determining the rate and the isomer preferences of monoacylglycerol hydrolysis. In contrast to wild-type enzymes that hydrolyzed 1- and 2-monoacylglycerols at similar rates, mutation of Cys242 to alanine caused a significant reduction in overall activity (maximal velocity, Vmax), particularly skewing the balanced hydrolysis of isomers to favor the 2-isomer. Molecular modeling studies indicate that this was caused by structural features unfavorable toward 1-isomers as well as impaired recognition of OH-groups in the glycerol moiety. Direct functional involvement of Cys242 in the catalysis was found unlikely due to the remote distance from the catalytic serine. Unlike C242A, mutation of Tyr194 did not bias the hydrolysis of 1- and 2-monoacylglycerols but significantly compromised overall activity. Finally, mutation of Cys242 was also found to impair inhibition of MAGL, especially that by fluorophosphonate derivatives (13- to 63-fold reduction in potency). Taken together, this study provides new experimental and modeling insights into the molecular mechanisms of MAGL-catalyzed hydrolysis of the primary endocannabinoid 2-arachidonoylglycerol and related monoacylglycerols.


PLOS ONE | 2014

Discovery of Triterpenoids as Reversible Inhibitors of α/β hydrolase Domain Containing 12 (ABHD12)

Teija Parkkari; Raisa Haavikko; Tuomo Laitinen; Dina Navia-Paldanius; Roosa Rytilahti; Miia Vaara; Marko Lehtonen; Sami Alakurtti; Jari Yli-Kauhaluoma; Tapio Nevalainen; Juha R. Savinainen; Jarmo T. Laitinen

Background α/β-hydrolase domain containing (ABHD)12 is a recently discovered serine hydrolase that acts in vivo as a lysophospholipase for lysophosphatidylserine. Dysfunctional ABHD12 has been linked to the rare neurodegenerative disorder called PHARC (polyneuropathy, hearing loss, ataxia, retinosis pigmentosa, cataract). In vitro, ABHD12 has been implicated in the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG). Further studies on ABHD12 function are hampered as no selective inhibitor have been identified to date. In contrast to the situation with the other endocannabinoid hydrolases, ABHD12 has remained a challenging target for inhibitor development as no crystal structures are available to facilitate drug design. Methodology/Principal Findings Here we report the unexpected discovery that certain triterpene-based structures inhibit human ABHD12 hydrolase activity in a reversible manner, the best compounds showing submicromolar potency. Based on structure activity relationship (SAR) data collected for 68 natural and synthetic triterpenoid structures, a pharmacophore model has been constructed. A pentacyclic triterpene backbone with carboxyl group at position 17, small hydrophobic substituent at the position 4, hydrogen bond donor or acceptor at position 3 accompanied with four axial methyl substituents was found crucial for ABHD12 inhibitor activity. Although the triterpenoids typically may have multiple protein targets, we witnessed unprecedented selectivity for ABHD12 among the metabolic serine hydrolases, as activity-based protein profiling of mouse brain membrane proteome indicated that the representative ABHD12 inhibitors did not inhibit other serine hydrolases, nor did they target cannabinoid receptors. Conclusions/Significance We have identified reversibly-acting triterpene-based inhibitors that show remarkable selectivity for ABHD12 over other metabolic serine hydrolases. Based on SAR data, we have constructed the first pharmacophore model of ABHD12 inhibitors. This model should pave the way for further discovery of novel lead structures for ABHD12 selective inhibitors.


Bioorganic & Medicinal Chemistry Letters | 2015

Loratadine analogues as MAGL inhibitors

Jayendra Z. Patel; Stephen Ahenkorah; Miia Vaara; Marek Staszewski; Yahaya Adams; Tuomo Laitinen; Dina Navia-Paldanius; Teija Parkkari; Juha R. Savinainen; Krzysztof Walczyński; Jarmo T. Laitinen; Tapio Nevalainen

Compound 12a (JZP-361) acted as a potent and reversible inhibitor of human recombinant MAGL (hMAGL, IC50=46 nM), and was found to have almost 150-fold higher selectivity over human recombinant fatty acid amide hydrolase (hFAAH, IC50=7.24 μM) and 35-fold higher selectivity over human α/β-hydrolase-6 (hABHD6, IC50=1.79 μM). Additionally, compound 12a retained H1 antagonistic affinity (pA2=6.81) but did not show cannabinoid receptor activity, when tested at concentrations ⩽ 10 μM. Hence, compound 12a represents a novel dual-acting pharmacological tool possessing both MAGL-inhibitory and antihistaminergic activities.


PLOS ONE | 2014

Biochemical and pharmacological characterization of the human lymphocyte antigen B-associated transcript 5 (BAT5/ABHD16A).

Juha R. Savinainen; Jayendra Z. Patel; Teija Parkkari; Dina Navia-Paldanius; Joona J. T. Marjamaa; Tuomo Laitinen; Tapio Nevalainen; Jarmo T. Laitinen

Background Human lymphocyte antigen B-associated transcript 5 (BAT5, also known as ABHD16A) is a poorly characterized 63 kDa protein belonging to the α/β-hydrolase domain (ABHD) containing family of metabolic serine hydrolases. Its natural substrates and biochemical properties are unknown. Methodology/Principal Findings Amino acid sequence comparison between seven mammalian BAT5 orthologs revealed that the overall primary structure was highly (≥95%) conserved. Activity-based protein profiling (ABPP) confirmed successful generation of catalytically active human (h) and mouse (m) BAT5 in HEK293 cells, enabling further biochemical characterization. A sensitive fluorescent glycerol assay reported hBAT5-mediated hydrolysis of medium-chain saturated (C14∶0), long-chain unsaturated (C18∶1, C18∶2, C20∶4) monoacylglycerols (MAGs) and 15-deoxy-Δ12,14-prostaglandin J2-2-glycerol ester (15d-PGJ2-G). In contrast, hBAT5 possessed only marginal diacylglycerol (DAG), triacylglycerol (TAG), or lysophospholipase activity. The best MAG substrates were 1-linoleylglycerol (1-LG) and 15d-PGJ2-G, both exhibiting low-micromolar Km values. BAT5 had a neutral pH optimum and showed preference for the 1(3)- vs. 2-isomers of MAGs C18∶1, C18∶2 and C20∶4. Inhibitor profiling revealed that β-lactone-based lipase inhibitors were nanomolar inhibitors of hBAT5 activity (palmostatin B > tetrahydrolipstatin > ebelactone A). Moreover, the hormone-sensitive lipase inhibitor C7600 (5-methoxy-3-(4-phenoxyphenyl)-3H-[1], [3], [4]oxadiazol-2-one) was identified as a highly potent inhibitor (IC50 8.3 nM). Phenyl and benzyl substituted analogs of C7600 with increased BAT5 selectivity were synthesized and a preliminary SAR analysis was conducted to obtain initial insights into the active site dimensions. Conclusions/Significance This study provides an initial characterization of BAT5 activity, unveiling the biochemical and pharmacological properties with in vitro substrate preferences and inhibitor profiles. Utilization of glycerolipid substrates and sensitivity to lipase inhibitors suggest that BAT5 is a genuine lipase with preference for long-chain unsaturated MAGs and could in this capacity regulate glycerolipid metabolism in vivo as well. This preliminary SAR data should pave the way towards increasingly potent and BAT5-selective inhibitors.

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Dive into the Teija Parkkari's collaboration.

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Tapio Nevalainen

University of Eastern Finland

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Juha R. Savinainen

University of Eastern Finland

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Jarmo T. Laitinen

University of Eastern Finland

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Tuomo Laitinen

University of Eastern Finland

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Antti Poso

University of Eastern Finland

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Dina Navia-Paldanius

University of Eastern Finland

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Jayendra Z. Patel

University of Eastern Finland

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Agnieszka A. Kaczor

Medical University of Lublin

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Susanna M. Saario

Scripps Research Institute

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