Medicinal Chemistry and Animal Pharmacology of Indoramin

Abstract

The role of α‐blockade in the treatment of hypertension can be reappraised in the light of a recently developed agent (indoramin) which overcomes the major drawbacks of earlier agents. The medicinal chemistry involved in the discovery and synthesis of indoramin is summarized. Highlights of the animal pharmacology of indoramin are outlined with reference to therapeutic utility as an antihypertensive agent. The mode of action of indoramin can be described as competitive post‐synaptic α‐adrenoceptor antagonism combined with myocardial membrane stabilization. Indoramin is an effective antihypertensive agent in man, without therapeutic problems associated with tachycardia, postural hypotension, tolerance, poor absorption, gastrointestinal disturbances, increased peripheral resistance or increased airways resistance. The pre‐clinical basis for these features has been reviewed.

Cutaneous arterial and venous alpha receptor blocking activity following intraduodenal indoramin to dogs

“…Moreover, indoramin did not reflexly elevate HR (Table 2) in the three animals in which the HR was comparable to that of the animals in the prazosin and vehicle treated groups. This finding is in agreement with those of Baum and Shropshire [I9751 and others in the dog [for references see Archibald et al, 1980Archibald et al, , 1981. (Hz).…”

“…Moreover, indoramin did not reflexly elevate HR (Table 2) in the three animals in which the HR was comparable to that of the animals in the prazosin and vehicle treated groups. This finding is in agreement with those of Baum and Shropshire [I9751 and others in the dog [for references see Archibald et al, 1980Archibald et al, , 1981. The saphenous veins and muscular arteries of man have a similar a,-adrenoceptor density and distribution to those of the saphenous and gracilis veins of the dog [Varia and Turner, 1973;Van Brummelen et al, 19861.…”

“…The inability of prazosin to prevent the rise in HR, when compared to the high dose of indoramin, may reflect the greater effect of indoramin on baroreceptor sensitization when compared to prazosin [Harron, 1986;Sasso and O'Connor, 19821 as well as the membrane stabilizing action of indoramin [Alps et al, 1972;Baum and Shropshire, 1975;Harron et al, 19841. The relative dissociation between the a,-adrenoceptor blocking and blood pressure lowering activities of indoramin suggests that an additional antihypertensive mechanism may be inherent in the indoramin molecule [Archibald, 1980[Archibald, , 1981. Dissociation of the hypotensive and a, adrenoceptor blocking activities of indoramin might occur if indoramin were a partial agonist at vascular a 1 adrenoceptors.…”

“…Prazosin was used as a standard a,-adrenoceptor antagonist because it is similar to indoramin in its 1) susceptibility to first dose metabolism, 2) tissue distribution, and 3) the time of onset of drug action following oral or id administration of a solution of commercially available drug [Graham and Pettinger, 1979;Holmes and Sorkin, 1986;Archibald, 1980Archibald, , 1981Archibald, , 1986Scriabine, 19801.…”

“…This study compares the relative arterial and venous a , adrenoceptor blocking activity of indoramin and prazosin, following intraduodenal (id) administration, in the canine hindpaw preparation perfused at constant flow, to their blood pressure lowering activity. Prazosin was used as a standard a,-adrenoceptor antagonist because it is similar to indoramin in its 1) susceptibility to first dose metabolism, 2) tissue distribution, and 3) the time of onset of drug action following oral or id administration of a solution of commercially available drug [Graham and Pettinger, 1979;Holmes and Sorkin, 1986;Archibald, 1980Archibald, , 1981Archibald, , 1986Scriabine, 19801.…”