Paciorek P M, Pierce V, Shepperson N B, Waterfall J F
Br J Pharmacol. 1984 May;82(1):127-34. doi: 10.1111/j.1476-5381.1984.tb16449.x.
The potencies and selectivities of a novel series of benzoquinolizines for the alpha 2-adrenoceptor have been investigated in the rat in comparison with yohimbine and indoramin. Peripheral postjunctional alpha 2- and alpha 1-adrenoceptor blockade was measured as the reversal of B-HT 933 and methoxamine-induced pressor responses, respectively, in the pithed rat. Peripheral prejunctional alpha 2-adrenoceptor blockade was measured as the reversal of B-HT 933-induced inhibition of an electrically evoked tachycardia in the pithed rat. Central alpha 2-adrenoceptor blockade was measured as a reversal of the hypotension induced in anaesthetized rats by central (i.c.v.) administration of clonidine. Wy 25309, Wy 26392, Wy 26703 and yohimbine (0.3-3 mg kg-1 i.v.) evoked dose-dependent shifts to the right of the dose-response curves to B-HT 933 whilst having minimal effects on the methoxamine dose-response curve. The selectivity for alpha 2-adrenoceptors increased with the dose of antagonist administered. In general, the order of selectivity was Wy 25309 greater than Wy 26392 greater than Wy 26703 greater than yohimbine. Indoramin (1 mg kg-1 i.v.) shifted the methoxamine pressor dose-response curve to the right without affecting the B-HT 933 dose-response curves, confirming its selective alpha 1-antagonist activity. Peripheral administration of all three benzoquinolizines (1-100 micrograms kg-1 i.v.) led to a dose-dependent reversal of the hypotension evoked by central administration of clonidine (500 ng i.c.v.). The reversal was incomplete, higher doses causing a further decrease in blood pressure. A similar degree of hypotension induced by the ganglion blocking agent chlorisondamine (1 mg kg- I i.v.) was not reversed by the benzoquinolizines. 9 It is concluded that Wy 25309, Wy 26392 and Wy 26703 are selective alpha 2-adrenoceptor antagonists which readily penetrate the CNS.
与育亨宾和吲哚拉明相比，在大鼠中研究了一系列新型苯并喹嗪类化合物对α2 -肾上腺素能受体的效价和选择性。在脊髓麻醉大鼠中，分别通过B - HT 933和甲氧明诱导的升压反应的逆转来测定外周节后α2 -和α1 -肾上腺素能受体阻滞。通过B - HT 933诱导的脊髓麻醉大鼠电诱发心动过速抑制的逆转来测定外周节前α2 -肾上腺素能受体阻滞。通过对麻醉大鼠中枢（脑室内）给予可乐定诱导的低血压的逆转来测定中枢α2 -肾上腺素能受体阻滞。Wy 25309、Wy 26392、Wy 26703和育亨宾（静脉注射0.3 - 3 mg·kg-1）引起剂量依赖性的向B - HT 933剂量反应曲线右侧的位移，同时对甲氧明剂量反应曲线影响最小。对α2 -肾上腺素能受体的选择性随着拮抗剂给药剂量的增加而增加。一般来说，选择性顺序为Wy 25309大于Wy 26392大于Wy 26703大于育亨宾。吲哚拉明（静脉注射1 mg·kg-1）使甲氧明升压剂量反应曲线向右移动，而不影响B - HT 933剂量反应曲线，证实了其选择性α1 -拮抗剂活性。所有三种苯并喹嗪类化合物外周给药（静脉注射1 - 100μg·kg-1）导致中枢给予可乐定（脑室内注射500 ng）诱发的低血压呈剂量依赖性逆转。逆转不完全，较高剂量导致血压进一步下降。神经节阻断剂氯异吲哚铵（静脉注射1 mg·kg-1）诱导的类似程度的低血压未被苯并喹嗪类化合物逆转。9得出结论，Wy 25309、Wy 26392和Wy 26703是选择性α2 -肾上腺素能受体拮抗剂，它们很容易穿透中枢神经系统。
