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STRUCTURE‐ACTIVITY RELATIONSHIPS OF CLONIDINE‐ AND TOLAZOLINE‐LIKE COMPOUNDS AT HISTAMINE AND α‐ADRENOCEPTOR SITES
Author(s) -
MALTA E.,
ONG JENNY S.B.,
RAPER C.,
TAWA PAULINE E.,
VAUGHAN G.N.
Publication year - 1980
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1980.tb07922.x
Subject(s) - histamine , receptor , clonidine , chemistry , vas deferens , stimulation , histamine receptor , tolazoline , pharmacology , endocrinology , medicine , biology , biochemistry , antagonist
1 Thirty clonidine‐ and tolazoline‐like compounds with differing phenyl ring substituents were tested for agonistic actions at histamine H 1 ‐receptors (guinea‐pig ileum), histamine H 2 ‐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). 2 All compounds were inactive at histamine H 1 ‐receptors, while 21 of the 30 compounds displayed varying stimulant activity at H 2 ‐receptors. 3 At post‐junctional α‐receptors all 30 compounds produced stimulant actions, whereas at prejunctional α‐receptors the compounds displayed either agonistic or antagonistic actions. 4 Thus structure‐activity relationships (SAR) could only be validated for histamine H 2 ‐ 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 H 2 ‐ than at α‐receptors. 5 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 H 2 ‐receptors, while α‐receptor stimulant activity is retained.