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 K_d for the binding was 1.7 ± 0.1 nM and the B_max 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 α-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 〉 Bay_a 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.