Displacement of [3H]clonidine binding by clonidine analogues in membranes from rat cerebral cortex.
[3H]Clonidine binds to membranes prepared from rat cerebral cortex by a high affinity saturable process. Using [3H]clonidine of specific activity 5.29 Ci/mmol the Kd for the binding was 1.7 +/- 0.1 nM and the Bmax 9.4 +/- 0.6 pmol/g (n = 5). The Hill coefficient for [3H]clonidine binding to rat cerebral cortex membranes was 0.97 +/- 0.05 (r > 0.93; n = 5) indicating an absence of +ve or -ve cooperativity. The clonidine metabolites 4-hydroxyclonidine; N(2,6-dichlorophenyl)guanidine; N(2,6-dichloro-4-hydroxyphenyl)guanidine; and 2-(2,6-dichlorophenyl)iminoimidazolidine-4-one and the metabolic intermediate 2-(2,6-dichlorophenylamino)imidazole were less effective displacers of [3H]clonidine binding than the parent compound. The first three compounds were more polar and the last two less polar than clonidine as judged by their apparent partition coefficients in octanol/phosphate buffer. Seven imidazolidine derivatives with known alpha-adrenoceptor activity were potent displacers of [3H]clonidine binding: the order of potency being 14,304-18 > naphazoline > clonidine > lofexidine and tiamenidine > CP18,534 > ST600 > ST91. Five 'clonidine-like' drugs displaced [3H]clonidine binding with an order of potency guanabenz > Baya 6781 > guanfacine > clonidine > xylazine >> FLA136. Apparent partition coefficients of the displacing agents have been measured in octanol/phosphate buffer and the importance of this factor is discussed with reference to their in vivo antihypertensive potency and potency as displacers of [3H]-clonidine binding.
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001665:Binding Sites; D002540:Cerebral Cortex / Q000378:metabolism*; D003000:Clonidine / Q000031:analogs & derivatives* / Q000378:metabolism*; D005260:Female; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000032:analysis; D013329:Structure-Activity Relationship; D014316:Tritium
D000959:Antihypertensive Agents; D007093:Imidazoles; D011942:Receptors, Adrenergic, alpha; D014316:Tritium; D003000:Clonidine