Selectivity and potency of 2‐alkyl analogues of the α2‐adrenoceptor antagonist idazoxan (RX 781094) in peripheral systems

• Published in: British journal of pharmacology 1984-11, Vol.83 (3), p.713-722
• Main Authors: Doxey, J.C., Roach, A.G., Strachan, Diane A., Virdee, Narinder K.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Catecholaminergic system; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1984.tb16225.x

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 α2‐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 α1‐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 (α2/α1) was RX 811005 > RX 801079 > RX 811054 > RX811033 > idazoxan > yohimbine. 4 In pithed rats, intravenous administration of all compounds fully reversed the prejunctional α2‐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 α2‐adrenoceptors was RX 811054 > RX811033 > idazoxan > yohimbine > RX811005 > RX 801079. In contrast, the rank order of antagonist potency against cirazoline pressor effects (vascular postjunctional α1‐adrenoceptors) was RX 811054 > RX 811033 > yohimbine > idazoxan > RX 811005 > RX 801079. The rank order of α2‐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 α2‐adrenoceptor antagonist potency or selectivity or both and furthermore, the weak partial α1‐adrenoceptor agonist properties of idazoxan can be removed.