Some pharmacological properties of Wy 27127 a more selective alpha2: alpha1-adrenoceptor antagonist than idazoxain in vitro

Abstract

Wy 27127 and idazoxan were approximately equipotent as antagonists at alpha 2-adrenoceptors as estimated by their ability to block clonidine-induced inhibition of electrically-evoked contractions of the rat isolated vas deferens. Idazoxan was seven times as potent as Wy 27127, as an antagonist at alpha 1-adrenoceptors as indicated by blockade of methoxamine-induced contractions of the rat isolated anococcygeus muscle. Thus, the alpha 2:alpha 1 selectivity ratio, as calculated from these tests was 407 for Wy 27127 and 76 for idazoxan. Wy 27127 and idazoxan were equipotent in enhancing stimulation-evoked overflow of tritium from rabbit isolated pulmonary arteries preloaded with [3H]-noradrenaline as expected for alpha 2-adrenoceptor antagonists. At higher concentrations both compounds reduced the stimulation-evoked contraction of the pulmonary artery but idazoxan was 15 times as potent as Wy 27127 in this respect. Neither compound had marked antagonist actions at 5-hydroxytryptamine (D), muscarinic, presynaptic dopamine or histamine (H1) receptors or at beta 1-adrenoceptors. Thus, idazoxan and Wy 27127 were equipotent alpha 2-adrenoceptor antagonists in vitro, however, the alpha 2:alpha 1 selectivity of Wy 27127 was considerably greater than that of idazoxan by virtue of weaker alpha 1-adrenoceptor antagonism.

.alpha.- and .beta.-Adrenoceptors: From the Gene to the Clinic. 2. Structure-Activity Relationships and Therapeutic Applications

“…(39) ICI 118,551 Although the basic (aryloxy)propanolamine nucleus must remain intact for significant /3-adrenoceptor an- Most of the classical /6-adrenoceptor antagonists have low affinity for the /^-adrenoceptor. Cyanopindolol (46) and iodocyanopindolol (47) appear to have higher affinity for the /Sa-adrenoceptor than other phenoxypropanolamines, although still lower than the affinity for the ß -or ^-adrenoceptors. Recently, two phenoxypropanolamines containing a tetralin substituent on the amino nitrogen, SR 58894A (48) and SR 59230A (49), have been shown to produce a selective blockade of/83adrenoceptors, with dissociation constants against SR 56811A in rat proximal colon (which contains /33adrenoceptors) that are 10-100-fold lower than those against isoproterenol or salbutamol (50) induced-activation of /3i-adrenoceptors (guinea pig atrium) or /32adrenoceptors (guinea pig trachea), respectively.30 Interestingly, several phenoxypropanolamines that are potent antagonists of ß -and /82-adrenoceptors also have a significant degree of agonist activity at the /83adrenoceptor.…”

Agonists and Antagonists Targeting the Different α2-Adrenoceptor Subtypes

“…A series of potent and selective α 2 -antagonists, including the berbane (CH-38083 (101) [180]), benzoquinolizine (WY 26703 (102) and WY 27127 (103) [181,182]), benzo [b]furoquinolizine (MK 467 (104) targeted as an antidiabetic [183], and MK-912 (105) acting at central and peripheral α 2 -ARs [184]), and isoquinonaphthyridine (delequamine or RS 15385-197 (106), endowed with an α 2 /α 1 selectivity ratio > 14,000 in binding experiments [185]) derivatives are structurally related to the family of yohimbanes.…”

Failure of selective antagonists (CH‐38083 and idazoxan) to distinguish between prejunctional and postjunctional α2‐adrenoreceptors

“…The search for selective a-adrenoreceptor antagonists was quickly successful in the case of the aladrenoreceptor with the development of prazosin (Cambridge, Davey & Massingham, 1977). Development of novel a,-adrenoreceptor antagonists such as benzodioxans (Chapleo, Myers, Butler, Doxey, Roach & Smith, 1983), benzoquinolizines (Lattimer, McAdams, Rhodes, Sharma, Turner & Waterfall, 1984;Bill, Boniface, Harann, McAdams, Lattimer & Rhodes, 1986) and berbanes (Vizi, Toth, Harsing, Szabo, Somogyi & Szantai, 1987) represents an advance towards an antagonist with a comparable degree of selectivity for the a,-adrenoreceptor. CH-38083 (7,8-(methylenedioxi)-14-ahydroxyalloberbane HCl), a potent member of berbane derivatives was found in vitro to be a highly selective a,-adrenoreceptor antagonist without a,-adrenoreceptor agonist activity (Vizi, Harsing, Gaal, Kapocsi, Bernath & Somogyi, 1986a).…”