Article date: August 1980
By: E. MALTA, JENNY S.B. ONG, C. RAPER, PAULINE E. TAWA, G.N. VAUGHAN, in Volume 69, Issue 4, pages 679-688
Thirty clonidine‐ and tolazoline‐like compounds with differing phenyl ring substituents were tested for agonistic actions at histamine H1‐receptors (guinea‐pig ileum), histamine H2‐receptors (guinea‐pig driven right ventricular strips), post‐junctional α‐adrenoceptors (rat desheathed vas deferens) and pre‐junctional α‐adrenoceptors (inhibition of sympathetic stimulation in guinea‐pig driven left atria).
All compounds were inactive at histamine H1‐receptors, while 21 of the 30 compounds displayed varying stimulant activity at H2‐receptors.
At post‐junctional α‐receptors all 30 compounds produced stimulant actions, whereas at prejunctional α‐receptors the compounds displayed either agonistic or antagonistic actions.
Thus structure‐activity relationships (SAR) could only be validated for histamine H2‐ and post‐junctional α‐receptor effects. These studies show that the most potent compounds are those with 2,6‐phenyl substituents in which rotation is restricted so that the two rings are aplanar. Electronic effects of the substituents have a greater influence on activity at H2‐ than at α‐receptors.
The major difference in SAR involves the influence of substituents in the 3, 4 or 5 positions on the phenyl ring. The presence of these substituents abolish significant activity at H2‐receptors, while α‐receptor stimulant activity is retained.
Thirty clonidine‐ and tolazoline‐like compounds with differing phenyl ring substituents were tested for agonistic actions at histamine H1‐receptors (guinea‐pig ileum), histamine H2‐receptors (guinea‐pig driven right ventricular strips), post‐junctional α‐adrenoceptors (rat desheathed vas deferens) and pre‐junctional α‐adrenoceptors (inhibition of sympathetic stimulation in guinea‐pig driven left atria).
All compounds were inactive at histamine H1‐receptors, while 21 of the 30 compounds displayed varying stimulant activity at H2‐receptors.
At post‐junctional α‐receptors all 30 compounds produced stimulant actions, whereas at prejunctional α‐receptors the compounds displayed either agonistic or antagonistic actions.
Thus structure‐activity relationships (SAR) could only be validated for histamine H2‐ and post‐junctional α‐receptor effects. These studies show that the most potent compounds are those with 2,6‐phenyl substituents in which rotation is restricted so that the two rings are aplanar. Electronic effects of the substituents have a greater influence on activity at H2‐ than at α‐receptors.
The major difference in SAR involves the influence of substituents in the 3, 4 or 5 positions on the phenyl ring. The presence of these substituents abolish significant activity at H2‐receptors, while α‐receptor stimulant activity is retained.
DOI: 10.1111/j.1476-5381.1980.tb07922.x
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