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The basic relationship between chemical structure and pharmacological activity of eight newly developed potential ultrashort-acting beta-adrenergic blockers was evaluated. The compounds studied are derivatives of arylcarbonyloxyaminopropanols and were prepared by four-step synthesis. All the compounds evaluated showed weak antiisoprenaline (beta-adrenergic receptor blocking) activity and antiarrhythmic (antiouabain) activity.

Using rat paw dextran-induced and carrageenan-induced edemas, the antiedematous activities of monohydrate of the diaquatetrakis(o-cresotato)dicopper(II) complex (CuoC) and the diaquabis(o-cresotato)zinc(II) complex (ZnoC) were assayed plethysmometrically. Dihydrate of the diaquabis(salicylato)copper(II) complex (CuS) and the diaquabis(salicylato)zinc(II) complex (ZnS) were used as the standards of comparison. All compounds were administered i.p. in a single dose of 50 mumol/kg body weight (calculated for the RCOO-fragment) 30 min before injecting the irritants. The antidextran/anticarrageenan activities of the species (expressed as a mean edema reduction) were found: CuoC 36/54%--ZnoC 59/65%--CuS 71/52%--ZnS 63/10%. The relationships between the coordination-chemical properties and the biological effects of the corresponding complexes are discussed.

Using rat paw dextran-induced and carrageenan-induced edemas, the antiedematous activities of dihydrate of diaquatetrakis(p-cresotato)dicopper(II) complex (CupC) and diaquabis(p-cresotato)zinc(II) complex (ZnpC) were assayed plethysmometrically. Dihydrate of diaquabis(salicylato)copper(II) complex (CuS) and diaquabis(salicylato)zinc(II) complex (ZnS) were used as standards of comparison. All compounds were applied i.p. in a single dose of 50 mumol/kg body weight (calculated for the RCOO-fragment) 30 min before injecting the irritant. The antidextran/anticarrageenan activities of the species (expressed as a mean edema reduction) were found: CupC 46/74%--ZnpC 50/26%--CuS 71/52%--ZnS 63/10%. The relationships between the coordination-chemical properties and the biological effects of the corresponding complexes are discussed.

Mononuclear aqua(aryloxyacetato)zinc(II) complexes of the composition [Zn(H2O)2(ROCH2COO)2] (R = phenyl, o-, m-, p-tolyl) were prepared as potential anti-inflammatory agents. The results of elemental analysis and parameters of IR spectra allow to classify the above-mentioned compounds to the group of carboxylatozinc(II) complexes with a distorted octahedral structure. They were assayed in rat paw carrageenan-induced edema and antiedematous effects were compared to those of free acids. Salicylic acid and its zinc(II) and copper(II) salts were used as the standards of comparison. All compounds were administered i.p. in a single dose of 50 mumol/kg body weight (calculated for the carboxylate fragment). In general, the zinc(II) complexes tested were clearly more effective (expressed as a mean edema reduction of 58-70-68-59%), including zinc(II) salicylate dihydrate (64%), than the uncomplexed acids (37-26-50-48%). Copper(II) salicylate tetrahydrate (60%) and salicylic acid (57%) exhibited comparable effects under the same conditions. The observed activities of the complexes are discussed in relation to their structures as well as to the coordination-chemical properties of the acidoligands under study.

In groups of mononuclear aqua(cresoxyacetato)copper(II) complexes of the composition [Cu(ROCH2COO)2(H2O)n] (R= 2- and 3-methylphenyl, n = 2; 4-methylphenyl, n = 3) and binu- clear phenazone(o-, m-, p-cresoxyacetato)copper(II) complexes of the composition [Cu2(ROCH2COO)4(phz)2] the anti-inflammatory activity was assayed in rat paw carrageenan-induced edema. The effects of the complexes were compared with each other and with those of the free acids. Salicylic acid and its cupric salt (tetrahydrate) were used as standards of comparison. All copounds were applied i.p. in a single dose of 50 mumol/kg body weight (calculated for the RCOO-fragment). In general, all Cu(II) complexes tested were clearly more effective (71-88%) than the corresponding free isomeric cresoxyacetic acids (47, 37, 45%), with the exception of diaquabis (o-cresoxyacetato)copper(II) complex (43%). Copper(II) salicylate tetrahydrate (57%) and salicylic acid (41%) were less active, too. The observed activities of complexes are discussed in relation to their structures.

Using rat paw dextran-induced and carrageenan-induced edemas, the anti-inflammatory activity of gallic acid (I), triacetylgallic acid (II) and monohydrate copper(II) triacetylgallate (III) was assayed. All compounds tested were applied i.p. in a single dose of 50 mumol/kg body weight, calculated for the RCOO-fragment. The average antiedematous activities in dextran/carrageenan edemas were decreasing in the following order: III (55.9/41.8%) > I (38.6/31.1%) > II (-3.4/13.3%). The relationship between the biological effects found and gallic acid as well as its structural derivatives is discussed.

Using rat paw carrageenan edema, the anti-inflammatory activity of nine selected arylcarboxylatocopper(II) aquacomplexes of the general composition Cu(RCOO)2.nH2O, where R represents 2-hydroxy-Y-methylphenyl, Y = 3 (n = 1.5), 4 (4) or 5 (2); 2-hydroxy-3,6-dimethylphenyl (n = 4); 2,5-diacetoxyphenyl (1); 2-methoxy-(1) and 4-methoxyphenyl (3); 2-furyl (3) and 2-thienyl (1), was assayed and compared to that of the free acids. Copper(II) salicylate tetrahydrate and salicylic acid were used as standards for comparison. All compounds were applied i.p. in a single dose of 50 mumol/kg body weight, calculated for the RCOO-fragment. m-Cresotato- (mean edema reduction 70%) and p-cresotatocopper(II) (80%) aquacomplexes were clearly more effective than copper(II) salicylate tetrahydrate (55%). The nonsubstituted hydroxyl of the salicylate skeleton of acidoligands is required for the activity of the complexes and of free acids tested. Isomeric cresotic acids (82-47-62%) and 2-furoic acid (48%) exhibited a higher effect than salicylic acid (42%). The relationship between the coordination-chemical properties and the biological effects of the complexes studied is discussed.

The basic pharmacological evaluation of five analogues of propafenone was the aim of the present paper. Antiarrhythmic activity of the compounds at 10(-5) mol.kg-1 was established in guinea-pigs using experimental arrhythmias induced by ouabain and aconitine. The beta-adrenolytic efficiency of the compounds was studied in the isolated spontaneously beating guinea-pig atria and expressed as pA2 values against isoprenaline tachycardia. All of the compounds studied were local-anaesthetically active and their indexes of efficiency were 1-5 fold higher in comparison with the standards cocaine and procaine. The acute toxicity of the compounds was within acceptable limits.

In a group of binuclear copper (II) complexes of the composition [Cu2(RCOO)4(H2O)2] (R = 2,4-diacetoxyphenyl (I), 2,5-diacetoxyphenyl (II) and 2,6-diacetoxyphenyl (III)), the anti-inflammatory activity was assayed in rat paw carrageenan-induced edema. Copper (II) salicylate tetrahydrate (IV) and salicylic acid were used as standards for comparison. All compounds were applied i.p. in a single dose of 50 mumol/kg body weight, calculated for the R-COO-fragment. The Cu(II) complexes tested were clearly more effective than the corresponding free diacetoxybenzoic acids, with an exception for the 2,5-diacetoxy derivative. The average anti-inflammatory activities of copper (II) complexes were decreasing in the following order: III (71.0%) = (70.6%) > IV (57.4%) > II (18.0%). Of the acids, only 2,6-diacetoxybenzoic acid (45.2%) was effective at the level of salicylic acid (44.9%). The relationship between the coordination-chemical properties and the biological effects of the complexes tested is discussed.

Using rat paw dextran edema, the antiexudative activity of the complexes of the composition Cu(RCOO)2.nH2O--R represents 2-hydroxy-Y-phenyl: Y = 3 (n = 1,5), Y = 4 (4), Y = 5 (2) or 2-hydroxy-3,6-dimethylphenyl (n = 4)--and of the corresponding uncomplexed acids was assayed. Salicylic and acetylsalicylic acids and their Cu(II) salts were used as standards of comparison. The compounds were administered i.p. in a single dose of 10 mg/kg body weight. In general, the acids were more effective than their copper(II) salts except for the pair m-cresotic acid--Cu(II) complex. Only p-cresotic acid (mean edema reduction 56%) and copper(II) m-cresotate tetrahydrate (43%) exhibited a biological activity comparable to those of salicylic acid (62%) and copper(II) salicylate tetrahydrate (70%). The observed activities of complexes are discussed in relation to their proposed structures.

A series of the new aminoalkyl esters of chlor-, methyl- and alkoxy carbanilates was synthesized. All the compounds prepared were found to exhibit antiarrhythmic activities comparable with those of mexiletine.

In a systematic study of the relationship between the chemical structure and beta-adrenolytic activity, eleven derivatives of the 4-alkoxysubstituted phenylcarbamic acids were prepared. The beta-adrenolytic efficiency of the compounds was studied in the isolated spontaneously beating guinea-pig atria and expressed as pA2 values against isoprenaline tachycardia. Negative chronotropic and antidysrhythmic activity were also evaluated. All of the compounds studied were local anesthetically active and their indexes of efficiency were 3-50 fold higher in comparison with standards cocaine and procaine. The acute toxicity of the compounds was within the acceptable limits.

The antipyretic activity of binuclear (diacetoxybenzoato)-copper(II) aquacomplexes [Cu2(2,Y-DAB)4(H2O)2] (Y = 4 and 5) as well as cupric acetylsalicylate [Cu2(AcSal)4] was assayed in a rabbit model of endotoxin-induced fever. The complexes and uncomplexed carboxylic acids (administered i.p. in a dose of 20 mg/kg) exhibited even a subnormothermic course in lowering of febrile animals' body temperature in the order: 2,5-diacetoxybenzoic acid (-0.09 degree C) < 2,4-diacetoxybenzoic acid (-0.35 degree C) < Cu(AcSal)2(-0.39 degree C) approximately equal to acetylsalicylic acid (-0.40 degree C) < Cu(2,4-DAB)2.H2O (-0.61 degree C) < Cu(2.5-DAB)2.H2O (-0.97 degree C). On the other hand, the mean value of untreated fevered animals was +0.67 degree C.

Evaluation of the antiulcer effects of a series of 2-piperidineethylesters of o-alkoxy-substituted phenylcarbamic acids were performed using two experimental models of gastric ulcers, e.g. induced by stress or by ligation of the pylor. It was found that these models were not identical. In the case of stress-induced ulcers, no experimental animal died as compared to the second experimental group with a 30% mortality rate due to the more frequent occurrence of ulcer perforations. Result similarities of both models could only be found with respect to the range of damage of the mucous membrane of the stomach. A premedication of rat with basic carbamates in the dose 20 mg.kg-1 p.o. resulted in a reduced incidence of stress- and ethanol-induced ulcerous lesions. The most significant antiulcer activity was found using compounds designated as the No. XIII, XVI and XIX. Pretreatment of rats with basic carbamates in the case of Shay ulcers has again resulted in a reduced range of ulcer lesions which was most expressive using compounds No. XVI and XIX.

Our previous experiments have suggested that besides the receptor cont and/or sensitivity a decrease of intracellular calcium level significantly participates in the mechanism of beta-blocker withdrawal 'rebound' phenomenon. This suggestion initiated studies in which possible changes in myocardial responsibility to cardioactive drugs were investigated in the condition of withdrawal of treatment with calcium entry blockers. The results showed increased cardiotoxicity of ouabain, aconitine and CaCl2, as well as an increased response of the heart to isoprenaline 24 hours after sudden cessation of treatment with verapamil (2 mg.kg-1 x 12 hours-1), diltiazem (3 mg.kg-1 x 12 hours-1) and nifedipine (0.5 mg.kg-1 x 12 hours-1). These results support the hypothesis of a common mechanism of the withdrawal syndrome of beta-lytics and calcium antagonists involving changes in intra-cellular calcium level. (Tab. 2, Fig. 4, Ref. 33.).

Using screening methods, the anti-inflammatory and antipyretic activities of mononuclear otahedral complexes [composition:Cu(2,YDHB)2.H2O;dihydroxybenzoate ion - DHB; Y(n)-4(8).5(4) and 6(8)] and the corresponding carboxylic acids were studied. On paw dextran edema (rats, an effective dose of 10 mg/kg), a higher efficacy of the complexes was found as compared with the acids. All compounds significantly reduced the endotoxin pyretic reaction (rabbits, in a single dose of 20 mg/kg; in the case of the first two complexes half-dose was administered). Marked toxic effects were determined for Cu(II) salts when they were administered i.p. The observed biological activities of complexes are discussed in relation to their proposed structures.

The synthesis of 24 compounds belonging to the group of dibasic substituted alkoxy phenyl carbamic acids is described. The compounds are characterized by relatively low acute toxicity and good local anaesthetic as well as antiarrhythmic activity.

During the systematic analysis of the relationship between chemical structure and local anaesthetic activity of basic esters of alkoxyphenylcarbamic acids, the diethylamino-isopropylester of 2-heptyloxyphenylcarbamic acid (carbisocaine) was synthesised and later extensively studied. This drug has been shown to be as active as procaine in skin anaesthesia in molar concentrations 416 times lower, and in corneal anaesthesia the drug parallels the standard agent cocaine in molar concentrations 251 times lower. The high relative local anaesthetic potency of carbisocaine and its low subcutaneous toxicity prompted wider pharmacological investigations in which the effects of carbisocaine on the central nervous system and the circulation were studied. The experiments showed that carbisocaine produced the typical effects of a local anaesthetic drug, i.e., stimulation of central nervous system, hypotension and a drop in the heart rate. The range of toxic doses and the cytotoxic activity of this interesting compound were also established.