John G. Topliss

New Class of Antihypertensive Agents

Effective antihypertensive agents of the benzothiadiazine series, devoid of diuretic activity, are described. There follows a method of synthesis and a description of the pharmacological activity of one of these substances

Chapter 30. Quantitative Structure-Activity Relationships in Drug Design

Publisher Summary Applications of quantitative structure–activity relationships (QSAR) approaches have been quite numerous in different fields, such as the central nervous system (CNS), cardiovascular, hormone, etc. A number of applications of QSAR are reported for chemotherapeutic agents. An interesting example is the use of QSAR in studying the mode of action of tuberculostatic drugs of the isonicotinic acid hydrazide type. In the hormone field, a detailed QSAR study of androst-4-en-3-one derivatives and their affinity for putative progesterone receptors led to the derivation of a six variable regression equation that satisfactorily predicted the affinities of other literature compounds. A novel feature of the analysis is the use of a surface area parameter for non-hydroxyl substituents as a measure of hydrophobic bonding of relatively non-polar groups. This review covers new developments concerning the methodological aspects of quantitative structure–activity relationships (QSAR), the physicochemical/structural parameters employed, applications of QSAR approaches to various problems, and the significance of the results in drug design. Finally, it describes an impressive case of the use of molecular models in conjunction with the knowledge of the structure of the receptor site to design compounds that should bind to and stabilize the deoxy conformation of human haemoglobin.

3-Haloalkyl-dihydrobenzothiadiazine dioxides as potent diuretic agents

Die Synthese und diuretische Aktivität von 3-Haloalkyl-dihydrobenzothiadiazin-dioxyden, insbesondere 3-Dichloromethyl-6-chlor-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazin-1,1-dioxyd, II,R = CHCl2, werden beschrieben.

Chapter 6. Antihypertensive Agents

Publisher Summary This chapter illustrates developments in the field of antihypertensive agents. The most significant development has been the Catapresan. This compound is designed and tested initially as a vasocostrictor. Preliminary clinical testing by intranasal administration produced marked prolonged sedation, a lowering of blood pressure, bradycardia, and dryness of the mouth. Two hundred and fifty imidazoline derivatives are synthesized and tested pharmacologically. Contraction of the nictitating membrane in cats, induced by preganglionic electrical stimulation, is not inhibited. No adverse effects on the myocardium are observed in experiments with the heart–lung preparation. No notable change in urine volume and excretion of electrolytes is seen but in renal and essential hypertension, a statistically significant rise of the serum concentration of sodium and chloride ions occurred. No notable change in urine volume and excretion of electrolytes is observed, but in renal and essential hypertension, a statistically significant rise of the serum concentration of sodium and chlrideions occurred. It has been found that the acutely administered drug produced a slowly developing hypertensive effect of long duration in spinal cats but under similar conditions in decerebrate animals, there is no observed effect on blood pressure. The chapter discusses the role of renin in renal hypertension and puts forward a hypothesis containing the novel proposal that the blood pressure lowering capacity of the kidney is directly proportional to its renin content.