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

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Abstract
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. 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. 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. 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. 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. 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. 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.

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