title: Antagonists that differentiate between alpha 2A-and alpha 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.
authors.affiliation: Pharmakologisches Institut, Freiburg, Germany.
authors.forename: A U
authors.initials: AU
authors.lastname: Trendelenburg
authors.forename: C A
authors.initials: CA
authors.lastname: Wahl
authors.forename: K
authors.initials: K
authors.lastname: Starke
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000378:metabolism / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D017660:Autoreceptors / Q000145:classification / Q000187:drug effects / Q000378:metabolism; D001572:Benzofurans / Q000378:metabolism / Q000494:pharmacology; D000068438:Brimonidine Tartrate; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D004146:Dioxanes / Q000378:metabolism / Q000494:pharmacology; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D019329:Idazoxan / Q000031:analogs & derivatives; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology; D007553:Isotope Labeling; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D010075:Oxathiins / Q000378:metabolism / Q000494:pharmacology; D011807:Quinolizines / Q000378:metabolism / Q000494:pharmacology; D011810:Quinoxalines / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D018341:Receptors, Adrenergic, alpha-2 / Q000145:classification / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014316:Tritium
chemical_list: D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D017660:Autoreceptors; D001572:Benzofurans; D004146:Dioxanes; D007093:Imidazoles; D010075:Oxathiins; D011807:Quinolizines; D011810:Quinoxalines; D018341:Receptors, Adrenergic, alpha-2; D014316:Tritium; C054290:L 657743; D000068438:Brimonidine Tartrate; C050877:benoxathian; C058525:2-methoxyidazoxan; C062597:efaroxan; D009638:Norepinephrine; D019329:Idazoxan