[Axelrod et al. (1958)][1] first described the enzyme-catalyzed O- methylation of catecholamines and other catechols in the late 1950s. The enzyme responsible for the O- methylation, catechol- O -methyltransferase (COMT; EC[2.1.1.6][2]),2 was partly purified and characterized by the same group ([

Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors.

Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial*

Heart failure is a major cause of death and disability. Impairments in blood circulation that accompany heart failure can be traced, in part, to alterations in the activity of the sarcoplasmic reticulum Ca2+ pump that are induced by its interactions with phospholamban, a reversible inhibitor. If phospholamban becomes superinhibitory or chronically inhibitory, contractility is diminished, inducing dilated cardiomyopathy in mice and humans. In mice, phospholamban seems to encumber an otherwise healthy heart, but humans with a phospholamban-null genotype develop early-onset dilated cardiomyopathy.

Phospholamban: a crucial regulator of cardiac contractility

ContextBecause acute decompensated heart failure causes substantial morbidity and mortality, there is a need for agents that at least improve hemodynamics and relieve symptoms without adversely affecting survival.ObjectiveTo assess the effect of a short-term intravenous infusion of levosimendan or dobutamine on long-term survival.Design, Setting, and PatientsThe Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) study was a randomized, double-blind trial comparing the efficacy and safety of intravenous levosimendan or dobutamine in 1327 patients hospitalized with acute decompensated heart failure who required inotropic support. The trial was conducted at 75 centers in 9 countries and patients were randomized between March 2003 and December 2004.InterventionsIntravenous levosimendan (n = 664) or intravenous dobutamine (n = 663).Main Outcome MeasureAll-cause mortality at 180 days.ResultsAll-cause mortality at 180 days occurred in 173 (26%) patients in the levosimendan group and 185 (28%) patients in the dobutamine group (hazard ratio, 0.91; 95% confidence interval, 0.74-1.13; P = .40). The levosimendan group had greater decreases in B-type natriuretic peptide level at 24 hours that persisted through 5 days compared with the dobutamine group (P<.001 for all time points). There were no statistical differences between treatment groups for the other secondary end points (all-cause mortality at 31 days, number of days alive and out of the hospital, patient global assessment, patient assessment of dyspnea at 24 hours, and cardiovascular mortality at 180 days). There was a higher incidence of cardiac failure in the dobutamine group. There were higher incidences of atrial fibrillation, hypokalemia, and headache in the levosimendan group.ConclusionDespite an initial reduction in plasma B-type natriuretic peptide level in patients in the levosimendan group compared with patients in the dobutamine group, levosimendan did not significantly reduce all-cause mortality at 180 days or affect any secondary clinical outcomes.Trial Registrationclinicaltrials.gov Identifier: NCT00348504

https://jamanetwork.com/journals/jama/articlepdf/206883/joc70043_1883_1891.pdf

Levosimendan vs Dobutamine for Patients With Acute Decompensated Heart Failure: The SURVIVE Randomized Trial

Background—We determined the short-term hemodynamic and clinical effects of levosimendan, a novel calcium-sensitizing agent, in patients with decompensated heart failure. Methods and Results—One hundred forty-six patients with New York Heart Association functional class III or IV heart failure (mean left ventricular ejection fraction 21±1%) who had a pulmonary capillary wedge pressure ≥15 mm Hg and a cardiac index ≤2.5 L · min−1 · m−2 were enrolled in a multicenter, double-blind, placebo-controlled study and randomized 2:1 to intravenous infusion of levosimendan or placebo. Drug infusions were uptitrated over 4 hours from an initial infusion rate of 0.1 μg · kg−1 · min−1 to a maximum rate of 0.4 μg · kg−1 · min−1 and maintained at the maximal tolerated infusion rate for an additional 2 hours. Levosimendan caused dose-dependent increases in stroke volume and cardiac index beginning with the lowest infusion rate and achieving maximal increases in stroke volume and cardiac index of 28% and 39%, respectively....

Acute Hemodynamic and Clinical Effects of Levosimendan in Patients With Severe Heart Failure

Binding of a new Ca2+ sensitizer, levosimendan, to recombinant human cardiac troponin C : A molecular modelling, fluorescence probe, and proton nuclear magnetic resonance study

Structure of the 1-36 Amino-Terminal Fragment of Human Phospholamban by Nuclear Magnetic Resonance and Modeling of the Phospholamban Pentamer

Calcium sensitizers are drugs which increase force development in striated muscle by sensitizing myofilaments to Ca2+. This can happen by increasing Ca2+ affinity of the regulatory domain of Ca2+ binding protein troponin C. High resolution crystal structures of two calcium binding proteins, calmodulin (Babu et al.: J. Mol. Biol. 203:191–204, 1988) and skeletal troponin C (Satyshur et al.: J. Biol. Chem. 263:1628–1647, 1988; Herzber et al.: J. Mol. Biol. 203:761–779, 1988), have recently been published. This makes it possible to model in detail the calcium-sensitizing action of drugs on troponin C.



In this study a model of human cardiac troponin C in three-calcium state has been constructed. When calcium is bound to calcium site II of cardiac troponin C an open conformation of the protein results, which has a hydrophobic pocket surrounded by a few polar side chains. Complexation of three drugs, trifluoperazine, bepridil, and pimobendan, to the hydrophobic pocket is studied using energy minimization techniques. Two different binding modes are found, which differ in the location of a strong electrostatic interaction. In analogy with the crystal structure of skeletal troponin C it is hypothezed that in cardiac troponin C an interaction occurs between Gln-50 and Asp-88, which has a long-range effect on calcium binding. The binding modes of drugs, where a strong interaction with Asp-88 exists, can effectively prevent the interaction between Asp-88 and Gln-50 in the protein, and are proposed to be responsible for the calcium-sensitizing properties of the studied drugs.

A model for human cardiac troponin C and for modulation of its Ca2+ affinity by drugs.

Quantitative structure-activity analysis was carried out for in vitro inhibition of rat liver catechol-O-methyl-transferase by a series of 1,5-substituted-3,4-dihydroxybenzenes. Linear regression analysis showed high correlation of inhibitory activity with both empirical electronic substituent parameters and quantum chemical descriptors. The combined effect of both substituents on lowering the pKa values of catechol hydroxyls and the energy of the lowest unoccupied molecular orbital appeared to be the most important determinant of increasing activity. Both substituents seemed to be also directly involved in binding. Hydrophobicity of the substituent at position 1 and the electronic structure of the substituent at position 5 were correlated with activity. A model for binding interactions of inhibitors was postulated on the basis of the QSAR equations derived.

QSAR and Binding Model for Inhibition of Rat Liver Catechol-O-Methyl-Transferase by 1,5-Substituted-3,4-Dihydroxybenzenes

Catechol and endogenous catechol derivatives are readily methylated by catechol O-methyltransferase (COMT). In contrast, many catechol derivatives possessing electronegative substituents are potent COMT inhibitors. The X-ray structure of the active site of COMT suggests that the methylation involves a lysine as a general base. The lysine can activate one of the catecholic hydroxyl groups for a nucleophilic attack on the active methyl group of the coenzyme S-adenosyl-l-methionine (AdoMet). We studied the effect of dinitrosubstitution of the catecholic ring at the semiempirical PM3 level on the methylation reaction catalysed by COMT. The electronegative nitro groups make the ionized catechol hydroxyls less nucleophilic than the corresponding hydroxyl groups of the non-substituted catechol. As a consequence, dinitrocatechol is not methylated but is instead a potent COMT inhibitor. The implications of this mechanism to the design of COMT inhibitors are discussed.

Martti Ovaska

Papers

Binding of a new Ca2+ sensitizer, levosimendan, to recombinant human cardiac troponin C : A molecular modelling, fluorescence probe, and proton nuclear magnetic resonance study

Structure of the 1-36 Amino-Terminal Fragment of Human Phospholamban by Nuclear Magnetic Resonance and Modeling of the Phospholamban Pentamer

A model for human cardiac troponin C and for modulation of its Ca2+ affinity by drugs.

QSAR and Binding Model for Inhibition of Rat Liver Catechol-O-Methyl-Transferase by 1,5-Substituted-3,4-Dihydroxybenzenes

A semiempirical study on inhibition of catechol O-methyltransferase by substituted catechols.