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Selectivity and potency of 2‐alkyl analogues of the α 2 ‐adrenoceptor antagonist idazoxan (RX 781094) in peripheral systems
Author(s) -
Doxey J.C.,
Roach A.G.,
Strachan Diane A.,
Virdee Narinder K.
Publication year - 1984
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.1476-5381.1984.tb16225.x
Subject(s) - idazoxan , yohimbine , chemistry , endocrinology , medicine , antagonist , potency , rauwolscine , agonist , prazosin , biology , receptor , in vitro , biochemistry
1 The profiles of four analogues of idazoxan have been examined at α‐adrenoceptors and the results compared to those obtained with idazoxan and yohimbine. The compounds possessed either a methyl (RX 801079), ethyl (RX 811033), n ‐propyl (RX 811054) or isopropenyl (RX 811005) group at the two position of idazoxan. 2 The rank order of antagonist potency against UK‐14,304 at prejunctional α 2 ‐adrenoceptors of the rat isolated vas deferens was RX 811054 > RX 811033 > idazoxan > RX 811005 > yohimbine = RX 801079. All compounds were competitive antagonists. 3 The rank order of antagonist potency against noradrenaline at postjunctional α 1 ‐adrenoceptors of the rat isolated anococcygeus muscle was RX 811054 = RX 811033 = idazoxan = yohimbine > RX 811005 = RX801079. All compounds were competitive antagonists. The rank order of α‐adrenoceptor selectivity (α 2 /α 1 ) was RX 811005 > RX 801079 > RX 811054 > RX811033 > idazoxan > yohimbine. 4 In pithed rats, intravenous administration of all compounds fully reversed the prejunctional α 2 ‐adrenoceptor agonist effects of clonidine and guanabenz on electrically‐induced contractions of the vas deferens and anococcygeus muscle respectively. 5 In pithed rats the rank order of antagonist potency against UK‐14,304 at cardiac prejunctional α 2 ‐adrenoceptors was RX 811054 > RX811033 > idazoxan > yohimbine > RX811005 > RX 801079. In contrast, the rank order of antagonist potency against cirazoline pressor effects (vascular postjunctional α 1 ‐adrenoceptors) was RX 811054 > RX 811033 > yohimbine > idazoxan > RX 811005 > RX 801079. The rank order of α 2 ‐adrenoceptor selectivity was RX 811033 = RX 801079 = RX 801005 > RX 811054 > idazoxan > yohimbine. 6 Although idazoxan produced contractions of the anococcygeus muscle and increased blood pressure in pithed rats, three of the analogues (RX 811005, RX 801079 and RX 811033) were inactive. 7 In conclusion, alkyl substitution in the 2‐position of idazoxan can enhance either α 2 ‐adrenoceptor antagonist potency or selectivity or both and furthermore, the weak partial α 1 ‐adrenoceptor agonist properties of idazoxan can be removed.