Antagonists that differentiate between ?2A- and ?2D-adrenoceptors

Abstract

Four antagonists were examined for their ability to differentiate alpha 2A-from the orthologous alpha 2D-adrenoceptors. The antagonists were (2S,12bS)1',3'-dimethylspiro(1,3,4,5',6,6',7,12b-octah ydro-2H- benzo[b]furo[2,3-a]quinolizine)-2,4'-pyrimidin-2'-one (MK912), 2-[2-(methoxy-1,4-benzodioxanyl)imidazoline (RX 821002), efaroxan and benoxathian. The alpha 2-autoreceptors in rabbit brain cortex were chosen as alpha 2A-and the alpha 2-autoreceptors in guinea-pig brain cortex as alpha 2D-adrenoceptors. Slices of the brain cortex were preincubated with 3H-noradrenaline and then superfused and stimulated electrically by brief pulse trains (4 pulses, 100 Hz) that led to little, if any, alpha 2-autoinhibition. 5-Bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14,304) was used as an alpha 2-adrenoceptor agonist. UK 14, 304 decreased the stimulation-evoked overflow of tritium. The antagonists shifted the concentration-inhibition curve of UK 14, 304 to the right in an apparently competitive manner. Dissociation constants of the antagonists were calculated from the shifts. MK 912, RX 821002 and efaroxan had markedly higher affinity for (guinea-pig) alpha 2D-adrenoceptors (pKd values 10.0, 9.7 and 9.1, respectively) than for (rabbit) alpha 2A-adrenoceptors (pKd 8.9, 8.2 and 7.6, respectively). Benoxathian had higher affinity for alpha 2A-(pKd 7.4) than for alpha 2D-adrenoceptors (pKd 6.9). Ratios calculated from the Kd values of the four compounds differentiated between alpha 2A and alpha 2D up to 100 fold. It is concluded that MK 912, RX 821002, efaroxan and benoxathian are antagonists with high power to differentiate alpha 2A-from alpha 2D-adrenoceptors.

Alcohol-Induced c-Fos Expression in the Edinger-Westphal Nucleus: Pharmacological and Signal Transduction Mechanisms

“…Behaviorally, this dose of ARC 239 was extremely sedative. Second, we used 5 and 10 mg/kg RX 821002, which has been shown to be a ␣ 2A/D -selective antagonist (Trendelenburg et al, 1996). When administered before alcohol, RX 821002 dose dependently diminished alcohol-induced c-Fos expression in EW neurons (Fig.…”

“…These experiments were followed up by tests of selective ␣-adrenoceptor antagonists on alcohol-induced c-Fos expression. Thereby, 10 min before a 2.4-g/kg alcohol injection, pretreatments of saline vehicle, ARC 239 (␣ 2B/C -selective; Tocris Cookson), or RX 821002 (␣ 2A/D -selective; Tocris Cookson) were administered (Trendelenburg et al, 1996;Callado and Stamford, 1999). To identify the involvement of the noradrenergic system in CDP-induced and morphine-induced EW c-Fos expression, these compounds were administered after yohimbine and RX 821002 (n ϭ 4/group), respectively.…”

RX 821002 as a Tool for Physiological Investigation of α2‐Adrenoceptors

“…The human, porcine and rabbit á 2A adrenoceptors are pharmacologically very similar, but the equivalent receptor in rat, mouse, guinea pig and cattle is distinctive, particularly in respect to its low affinity for yohimbine (1,9,30). In acknowledgement of these differences, this receptor is sometimes known as á 2D (107). All types have been found in the CNS, but the dominant á 2 -receptor in the brains of all species is type A, accounting for up to 90% of á 2 -binding in some brain regions (109,110).…”

Rilmenidine reveals differences in the pharmacological characteristics of prejunctional α2‐adrenoceptors in the guinea‐pig, rat and pig

“…It should be noted, however, that a clear a 2D /a 2A -adrenoceptor split for the agonist/ antagonist action of rilmenidine may not be true of all species. For example, rilmenidine was originally reported as an agonist at pre-junctional a 2 -adrenoceptors regulating noradrenaline release in the rabbit isolated saphenous vein (Verbeuren et al, 1989), a species reported to possess the a 2A -adrenoceptor subtype Trendelenburg et al, 1996b). More recently, Urban et al (1995) reported that rilmenidine reduced plasma noradrenaline levels in pithed rabbit stimulated electrically to elevate blood pressure, an e ect presumably mediated by activation of pre-junctional a 2 -adrenoceptors.…”

“…However, pharmacological di erences have been revealed either by determining the rank order of potency of an extensive range of antagonists, followed by comparison with known preparations based on correlation coe cient (Renouard et al, 1994;O'Rourke et al, 1994;Trendelenburg et al, 1995), or establishing the potency ratio for pairs of antagonists (Molderings & GoÈ hert, 1995;Trendelenburg et al, 1996a). For example, phentolamine has been shown to be approximately 5 fold more potent than rauwolscine at a 2D -adrenoceptors (Funk et al, 1995;Trendelenburg et al, 1996b;Wahl et al, 1996), while the reverse is true at a 2A -adrenoceptors (Trendelenburg et al, 1994;Molderings & GoÈ hert, 1995). To date, however, there have been no studies concerning the comparative e ect of putative agonists at a 2A -and a 2D -adrenoceptors.…”