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The diuretic and saluretic effect of the benzothiadiazine derivative 3-(a-methylbenzyl)-6-chlore-7-sulfamoyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-diozide (bemetizide) and the pteridine derivative 2,4,7-triamino-6-phenylpteridine (triamterene) were compared with those of their combination in the animal experiment on rats. Dose-effect relationships at a ratio of 1:2. The combination displayed marked advantages over the individual substances. The mixing proportion of 1:2 may be considered suitable.

The present experiments were performed to gain information on changes in various organ flow rates during i.v. infusion of vasodilating substances. The microsphere method with the reference sample technique was used in rats to measure simultaneously different organ flow rates. The detection of the spheres (non-radioactive) was performed by macerating the tissues and counting samples under the microscope. As only one microsphere-infection per animal was performed, an untreated experimental group served as a control. The cardiac output was measured in a separate series. The effects of isoproterenol, pentoxifylline, bencyclane, acetylcholine, and dihydroergotoxine (mixture of 3 compounds, Hydergin) consisted of flow increases in several organs while the flow in others remained nearly unchanged. Only during the action of sodium nitroprusside the flow values were found decreased or remained unchanged. This substance led to decreased cardiac output, whereas that in the other groups was unchanged or raised. The experiments point to quantitatively different reactions on cardiac output distribution during application of the vasodilating substances tested.

1-Benzyl-1-(3-dimethylaminopropoxy)cycloheptane (bencyclane-hydrogen-fumarate; Fludilat) in a concentration of 10-2 M effects an increase in the O2 consumption and the formation of CO2 in a 10% bovine lens homogenate. This effect is even increased if the glucose-substrate supply is raised from 25 mM to 37 mM. Investigations on the concentrations at ATP, ADP and AMP show that bencyclane is able to stabilize the physiologic distribution pattern of the three free adenine nucleotides. Further, the observed changes in the distribution pattern indicated that the fumaric acid rest of bencyclane may serve as a substrate for this reaction in the same way as fumarate.

The Michaelis-Menten constant for fumarase (E.C. 4.2.1.2) has been determined by measuring the enzyme activity by the spectrophotometric method of Racker, which depends on the formation or disappearance of the double bond of fumaric acid. When using Na2-fumarate or bencyclan hydrogenfumarate (Fludilat), respectively, as a substrate, a KM-value of 1.3 X 10(-3) M was found for both substances. In a linked assay where the formation of NADH in the reaction of fumarate leads to malate leads to oxaloacetate was used as a parameter for the reaction rate, a KM-value of 1.35 X 10(-3) M was found.

Compound 5,11-dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one dihydrochloride (pirenzepine, L-S 519) represents a new type of drug in ulcer therapy. It has been selected for broad clinical investigations because of its outstanding pharmacological profile. Pirenzepine is devoid of any central activity despite certain structural similarities in relation to psychotropic tricyclic compounds. The extraordinary pharmacokinetic and pharmacodynamic behaviour of this compound can be easily derived from its inherent physicochemical properties: The inability to pass the blood-brain barrier as well as its inability to activate the unspecific and specific psychotropic receptors is due to thermodynamic factors.

The crystal structures of the antiulcer drug 5,11-dihydro-11-[(4-methyl-1-piperazinyl) acetyl]-6H-pyrido[2,3-b] [1,4]benzodiazepin-6-one dihydrochloride (pirenzepine dihydrochloride, L-S 519 CL 2, Gastrozepin) and its monoprotonated form (pirenzepine monohydrochloride, L-S 519 CL) were determined by X-ray analysis. Molecular mechanics (MMPI) and semiempirical quantum chemical (MNDO) calculations showed that the calculated minimum energy conformations of the tricycle and of the exocyclic amide group are in agreement with the crystal structures. The conformational energies of pirenzepine as a function of four important torsional angles were calculated using different semiempirical quantum chemical methods with the CNDO/2 (complete neglect of differential overlap)-, MNDO (modified neglect of diatomic overlap)- and PCILO (perturbative configuration interaction using localized orbitals)-approximations. The conformation of one local energy minimum corresponds closely to the crystal structure of pirenzepine monohydrochloride. This conformation has a spatial arrangement which is analogous to a single consistent conformation known from the literature of 24 anticholinergic agents determined from their crystal structures by a computer graphics analysis. On the other hand there are no structural relationships of any low energy conformation of pirenzepine to conformations of other classes of tricyclic compounds which could rationalize their antidepressant, neuroleptic or antihistaminic activity. This finding explains the absence of any central effect of pirenzepine following intracerebral application. The computational elucidation of the conformational requirements for the interaction with the muscarinic receptors may be helpful for the interpretation of the selectivity of pirenzepine within the muscarinic system.