wy-26392 and azepexole

The potencies of a number of selective alpha 2-adrenoceptor antagonists have been measured in preparations from four species. In the rat vas deferens, the newer synthetic antagonists Wy 25309, Wy 26392, Wy 26703 and RX 781094 were more potent than the alkaloid yohimbine in blocking a clonidine-induced inhibition of an electrically evoked twitch response. In the rabbit vas deferens yohimbine was substantially more potent than the synthetic antagonists in reversing the action of clonidine. Yohimbine was also more potent than the synthetic antagonists in blocking the B-HT 933-induced contractile responses of the dog saphenous vein and preventing adrenaline-induced aggregation of human platelets. Together with previously published data derived from tritium overflow studies on rabbit pulmonary arteries and displacement of [3H]-rauwolscine binding from rat cerebral cortex and human platelets, the results suggest that the adrenoceptor currently labelled alpha 2 may not be a single entity.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Azepines; Clonidine; Dioxanes; Dogs; Humans; Idazoxan; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth, Vascular; Platelet Aggregation; Quinolizines; Rabbits; Rats; Rats, Inbred Strains; Saphenous Vein; Species Specificity; Vas Deferens; Yohimbine

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.

Topics: 2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy-; Action Potentials; Animals; Azepines; Chlorisondamine; Clonidine; Female; Indoramin; Methoxamine; Quinolizines; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha