Studies on quinoxaline derivatives. Synthesis of quinoxalylamino-1,3-diazacycloalkanes with potential hypotensive activity.

A series of quinoxalylamino-1,3-diazacycloalkanes was obtained by the reaction of the corresponding substituted aminoquinoxalines with alcohols and amines. The effect of selected compounds on the blood pressure of anaesthesized normotensive rats was studied.

Studies on pyrazine derivatives. XXX. Synthesis of pyrazinylamino-1,3-diazacycloalkanes of potential circulatory activity.

A series of pyrazinylamino-1,3-diazacycloalkanes was obtained by reaction of the corresponding substituted aminopyrazines with aliphatic amines. Selected compounds were studied with respect to their potential circulatory activity. The effect on the blood pressure, isolated rat tail artery and heart atria, and an influence on the human blood platelet aggregation were investigated.

Synthesis, structure and biological activity of 1,2,4-triazolo-1,3-thiazine derivatives.

A group of condensed triazole-thiazine derivatives (2a-i, 3b, 3j) was obtained in reaction of the corresponding 5-substituted 1,2,4-triazole-3-thiones (1a-j) with epichlorohydrin in alkaline medium. The structure of the compounds synthesized was confirmed by spectral and roentgenographic methods. Tuberculostatic and circulatory activities of the compounds were also studied.

New antagonists of the vasopressin receptor mediated contraction in rat tail artery.

A perfused isolated rat tail artery preparation was employed to study antagonistic properties of four newly synthesized arginine-vasopressin (AVP) analogues against the V1 receptor. The activity of the agents SCATyr(Me)AVP, OCATyr(Me)AVP, OCAAVP and SCAAVP was related to that of a recognized antagonist d(CH2)5Tyr(Me)AVP. SCATyr(Me)AVP elicited outstanding antagonistic properties by blocking at concentration of 10(-7) M nearly completely the constrictory activity of AVP. At concentration of 10(-9) M the agent inhibited the AVP-induced constriction of artery about 40 times more effectively than the oxytocin (OXT)-induced constriction. The results obtained prove the validity of the structure-activity relationship based search for new potent V1 receptor antagonists.

Synthesis and pharmacological activity of 5-substituted-s-triazole-3-thiols.

Two subgroups of 5-substituted triazoles were synthesized: derivatives of 3(3-substituted-amino-2-hydroxypropylthio)-5-substituted-4H-1,2,4- triazole and derivatives of N-substituted amides of 5-substituted-s-(1,2,4-triazole-3)thioglycolic acid. Selected members of the two subseries were tested pharmacologically. The blood pressure lowering effect in anaesthetized normotensive rats was weak to moderate. More pronounced was the inhibitory effect against adrenaline induced human blood platelet aggregation. In experiments on isolated rat heart atria and on isolated rat tail artery the activity of the agents was much weaker than in the case of known beta or alpha adrenoceptor antagonists. Generally, the chance to find a potential antihypertensive agent within the group studied seems to be low. Antiaggregatory activity of the compounds deserves further studies.

A search for new antihypertensive agents. II. Circulatory activity and selection of structures among 2-methylbenzimidazole derivatives.

A series of twelve 2-methylbenzimidazole derivatives was prepared and their effect on the contraction of isolated rat tail artery, on beating rate and amplitude of isolated rat heart atria, on human blood platelet aggregation, and on blood pressure in urethane-anesthetized normotensive rats were tested. Numerical measures of pharmacodynamic activity were quantitatively related to the changes in chemical structure of the agents. Conclusions are drawn about the mechanism of pharmacodynamic action of 2-methylbenzimidazole derivatives, which is not executed directly through the adrenergic system. The further direction of synthesis is established basing on the results obtained.

Furosemide antagonizes the contractile response to noradrenaline on isolated rat tail artery.

To determine the effect of furosemide (FUR) on the noradrenaline (NA) contraction of arteries, experiments were performed on isolated rat tail arteries according to Nicholas. FUR (300 mumol/l, 3 mmol/l) as well as Ca2+ transport system inhibitor, verapamil (VER), decreased the NA contractile force and FUR (3 mmol/l) antagonized the effect of VER (10 and 100 nmol/l). Calculated dose ratios according to Stephenson indicated that FUR and VER compete not only with NA but with each other. FUR decreased Ca2+ concentration in rat arteries studied in vivo by atomic absorption spectrophotometric method as well. It could be assumed that FUR depresses the sensitivity to NA and antagonizes NA induced contraction of arteries acting on transmembrane Ca2+ transport system.

Structure and alpha-adrenergic activity of pyrazinimidazolines.

The effects of newly synthetized pyrazinimidazolines on the contraction of isolated rat tail artery and on the chronotropic action of rat atria as well as the effects on blood pressure in anaesthetized rats were determined. The structure-activity relationships were studied, including standard imidazoline drugs. Starting from practically inactive derivatives the step-by-step structural modifications have been made resulting in markedly active chemical congeners, which were designed, synthetized and tested pharmacologically.

A search for new antihypertensive agents. I. Alpha-adrenergic activity and selection of structures among pyrazine substituted imidazolines.

A group of new pyrazinylimidazolines was prepared and their effect on the contraction of isolated rat tail artery as well as their effect on blood pressure in urethane anesthetized normotensive rats were tested. The biological responses were compared to those elicited by standard imidazoline drugs and structure-activity relationships were analysed. The new chemical derivatives were subsequently synthetized and tested pharmacologically. Basing on the experimental results obtained and comparing these to the reported data on arylimidazolines the following suggestions have been put forward concerning the further modifications of alpha-adrenergically active pyrazinylimidazolines: 1) a distance of about 5 A should separate imidazoline nitrogen and pyrazine nucleus, 2) bond refractivity of the separating bridge should be above 5.33, 3) hydrophobicity of substituents in pyrazine ring must be possibly high.

Possible role of ascorbic acid in catecholamines-stimulated Na+-K+-adenosine triphosphatase activity of the central nervous tissues.

Using EDTA and illuminated bovine retinas homogenate it has been found that Na+-K+-ATPase was stimulated by noradrenaline (NA), dopamine (DA), cAMP and dibutyryl cAMP. Phentolamine, an alpha adrenergic antagonist and INPEA, a beta adrenergic antagonist used at the same concentrations as catecholamines (CA) depressed the stimulatory effect of NA. Phentolamine increased the stimulatory effect of DA but INPEA inhibited it. It is proposed, therefore, that DA acts on retina Na+-K+-ATPase by putative DA receptors regulated by adrenergic antagonists. Ascorbic acid (AA), 0.125-1.0 mM depressed Na+-K+-ATPase activity of retinas, rat brain cortex and cerebellum homogenates. The results are consistent with the hypothesis that CA and AA can exert their effects in the presence of EDTA. In the retina the effects of CA is mediated by cAMP and alpha receptor influencing process. AA is postulated as a factor regulating the stimulation of CA on Na+-K+-ATP-ase and thereby the turnover of neurotransmitters in the central nervous system tissues.