Doxey J C, Roach A G, Strachan D A, Virdee N K
Br J Pharmacol. 1984 Nov;83(3):713-22. doi: 10.1111/j.1476-5381.1984.tb16225.x.
The profiles of four analogues of idazoxan have been examined at alpha-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 alpha 2-adrenoceptors of the rat isolated vas deferens was RX 811054 greater than RX 811033 greater than idazoxan greater than RX 811005 greater than yohimbine = RX 801079. All compounds were competitive antagonists. The rank order of antagonist potency against noradrenaline at postjunctional alpha 1-adrenoceptors of the rat isolated anococcygeus muscle was RX 811054 = RX 811033 = idazoxan = yohimbine greater than RX 811005 = RX801079. All compounds were competitive antagonists. The rank order of alpha-adrenoceptor selectivity (alpha 2/alpha 1) was RX 811005 greater than RX 801079 greater than RX 811054 greater than RX 811033 greater than idazoxan greater than yohimbine. In pithed rats, intravenous administration of all compounds fully reversed the prejunctional alpha 2-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 alpha 2-adrenoceptors was RX 811054 greater than RX 811033 greater than idazoxan greater than yohimbine greater than RX 811005 greater than RX 801079. In contrast, the rank order of antagonist potency against cirazoline pressor effects (vascular postjunctional alpha 1-adrenoceptors) was RX 811054 greater than RX 811033 greater than yohimbine greater than idazoxan greater than RX 811005 greater than RX 801079. The rank order of alpha 2-adrenoceptor selectivity was RX 811033 = RX 801079 = RX 801005 greater than RX 811054 greater than idazoxan greater than 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 alpha 2-adrenoceptor antagonist potency or selectivity or both and furthermore, the weak partial alpha 1-adrenoceptor agonist properties of idazoxan can be removed.
已对异唑烷的四种类似物在α-肾上腺素受体上的情况进行了研究，并将结果与用异唑烷和育亨宾获得的结果进行了比较。这些化合物在异唑烷的2位上分别具有甲基（RX 801079）、乙基（RX 811033）、正丙基（RX 811054）或异丙烯基（RX 811005）基团。在大鼠离体输精管的突触前α2-肾上腺素受体上，对UK-14,304的拮抗剂效价顺序为：RX 811054＞RX 811033＞异唑烷＞RX 811005＞育亨宾 = RX 801079。所有化合物均为竞争性拮抗剂。在大鼠离体肛门尾骨肌的突触后α1-肾上腺素受体上，对去甲肾上腺素的拮抗剂效价顺序为：RX 811054 = RX 811033 = 异唑烷 = 育亨宾＞RX 811005 = RX801079。所有化合物均为竞争性拮抗剂。α-肾上腺素受体选择性（α2/α1）的顺序为：RX 811005＞RX 801079＞RX 811054＞RX 811033＞异唑烷＞育亨宾。在去大脑大鼠中，静脉注射所有化合物分别完全逆转了可乐定和胍那苄对输精管和肛门尾骨肌电诱发收缩的突触前α2-肾上腺素受体激动剂作用。在去大脑大鼠中，对心脏突触前α2-肾上腺素受体上的UK-14,304的拮抗剂效价顺序为：RX 811054＞RX 811033＞异唑烷＞育亨宾＞RX 811005＞RX 801079。相反，对可乐唑啉升压作用（血管突触后α1-肾上腺素受体）的拮抗剂效价顺序为：RX 811054＞RX 811033＞育亨宾＞异唑烷＞RX 811005＞RX 801079。α2-肾上腺素受体选择性顺序为：RX 811033 = RX 801079 = RX 801005＞RX 811054＞异唑烷＞育亨宾。尽管异唑烷在去大脑大鼠中引起肛门尾骨肌收缩并升高血压，但其中三种类似物（RX 811005、RX 801079和RX 811033）无活性。总之，异唑烷2位上的烷基取代可增强α2-肾上腺素受体拮抗剂效价或选择性或两者兼具，此外，异唑烷微弱的部分α1-肾上腺素受体激动剂特性可被消除。
