Cardiotonic activities

When, aiming at its cardiotonic activity (stimulant), the 2,5-dioxo-l,2,5,6,7,8-hexahydro-3-cyano-6-bromoquinoline is made to react with different thioamides, the appropriate 6-substituted 8,9-dihydro- (R = cyanomethyl-, 2-oxopyrrolidinyl-methyl-, 2-oxohexahydroazepinomethyl-, and thioxopyrrolidinylmethyl-) (94KFZ43) or (R = H, Me, NH2, NH/S ) (86JAP(K)1, 89H1517) thiazolo[4,5-/Iquinolines 37 or oxidized products (89H1517) are produced. 

Assay results with the two new 1,2-cis (ft-d) cardenolides show enhanced activity as compared with the two unnatural, a-D-rhamnosides. They have potencies that fall well within the range for those of the naturally occurring cardenolides. These results support the postulate that the a-D-glycosidic linkage in cardenolides containing D-sugars is unfavorable for cardiotonic activity. 

The pumiliotoxins, alio- and homopumiliotoxins, are alkaloids isolated from the skin of amphibians, such as neotropical frogs of the Dendrobatidae family, and are believed to serve as a chemical defence against predators. These natural products have interesting pharmacological properties, including myotonic and cardiotonic activities. 

Another class of these amphibian alkaloids, the pumiliotoxins, contain an alkylidene side chain on C-6 of the indolizidine ring (Table 2). Due to their myotonic and cardiotonic activity, and challenging structure, they also have been the object of synthetic interest. A review points out the state of the art at the beginning of the decade <1996CRV505>. 

For a long period, a butenolide or a 2-pyrone ring in the 17y -position of the steroid system has been considered an essential feature for digitalis-like cardiotonic activity. However, it turned out that the unsaturated lactone ring can be replaced without loss of activity by some other moieties, including the 4-pyridazinyl group. 

It has been claimed that cardiotonic activity is retained upon replacement of the pyridone moiety in the amrinone molecule by a 3(2 /)-pyridazinone system (9) [7]. Moreover, the patent literature covers various cardiotonic 6-(pyridyl)-3(2//)-pyridazinones and 4,5-dihydro congeners as exemplified by (10), which have been developed in the United States [8-11], Also 3-amino-... 

From this series, compound MCI-154 (CAS 98326-33-1) (30) has been investigated in detail [95,96]. In vivo studies (anaesthetized dogs) revealed that doses of 0.3-100 tg/kg (i.v. administration) of MCI-154 produce dose-dependent increases in dF/dtmax and cardiac output, and decreases in arterial blood pressure and total peripheral resistance. The positive inotropic effect of (30) has been found to be superior to that exhibited by amrinone and milrinone [97,98]. It has been stated that MCI-154 exerts its activity probably by increasing the calcium-ion sensitivity of the contractile protein system of the cardiac skinned fibres [99,100]. A recent investigation suggests that inhibition of phosphodiesterase III is an important component of its cardiotonic activity [101]. 

Theophylline and other methylxanthines also display a pharmacological effect on a number of other organ systems. Of course the most pronounced effect is relaxation of smooth musculature in the respiratory tract. However, theophylline is a CNS stimulant, and it lowers arterial blood pressure, increases diuresis, displays cardiotonic activity, and has a specific effect on the gastrointestinal tract. The effects listed are the most frequently encountered side effects upon taking theophylline as a broncholytic. 

Cardiotonic activity. Petroleum ether fraction chromatographed and fraction eluted with chloroform, administered by perfusion at a concentration of 0.20 mg/mL, was inactive on the guinea pig heart . 

Generally antidepressant, antitubercular, choleretic, diuretic, antimicrobial, antiviral, and cardiotonic activity Antibacterial (Staphylococcus aureus) Antifungal... 

One way of addressing the issue of a lack of precision in the locations of functionally important side chains is to determine the range of conformational space available to them in different ligands. To this end, we undertook a detailed comparison of the structures of AP-A and AP-B in solution [47]. This proved to be a useful exercise both in terms of defining the positions of side chains known to be important for cardiotonic activity and identifying neighboring residues which might also be involved [47]. 

When AP-A was treated with trypsin only the Argl4 to Glyl5 peptide bond was cleaved [56]. The resulting derivative lacked cardiotonic activity but its binding affinity for the rat brain sodium channel was reduced by less than an order of magnitude (Llewellyn LE et al., unpublished results). Its overall structure, as... 

Endoproteinase LysC cleaved AP-A between Lys37 and Ala38 to yield a derivative with cardiotonic activity an order of magnitude lower than that of the parent molecule (Monks SA and Norton RS, unpublished results). This reduction in activity could be a consequence of local conformational perturbations. Treatment of AP-B with carboxypeptidase removed Lys49, resulting in only a two-fold reduction in cardiotonic activity (Monks SA and Norton RS, unpublished results). 

Japanese researchers synthesized several derivatives of 5,6,7,8-tetrahydro-3(2//)-isoquino inones with cardiotonic activity. Of these compounds, 83 is one of the most potent positive ionotropic agents (89JMC351). 

Qualitatively, the cardiotonic activity of the glycosides resides in the aglycon portion,2 which is steroidal in nature. The most widely studied aglycons are digitoxigenin [3/3,14/9-dihydroxy-5/9-card-20(22) -enolide (1) ],... 

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