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[ 3 H]‐MK 912 binding delineates two α 2 ‐adrenoceptor subtypes in rat CNS one of which is identical with the cloned pA2d α 2 ‐adrenoceptor
Author(s) -
Uhlén Staffan,
Xia Yun,
Chhajlani Vijay,
Felder Christian C.,
Wikberg Jarl E.S.
Publication year - 1992
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1992.tb14446.x
Subject(s) - rauwolscine , oxymetazoline , guanfacine , prazosin , yohimbine , alpha (finance) , chemistry , adrenergic receptor , endocrinology , alpha 2 adrenergic receptor , medicine , receptor , biology , antagonist , biochemistry , clonidine , construct validity , nursing , patient satisfaction
1 Simultaneous computer modelling of control and guanfacine‐masked [ 3 H]‐MK 912 saturation curves as well as guanfacine competition curves revealed that the drugs bound to two α 2 ‐adrenoceptor subtypes in the rat cerebral cortex with very different selectivities. These α 2 ‐adrenoceptor subtypes were designated α 2A and α 2C . The K d value of [ 3 H]‐MK 912 for the α 2A ‐subtype was 1.77 n m and for the α 2C ‐subtype 0.075 n m ; the receptor sites showing capacities 296 and 33 fmol mg −1 protein, respectively. The K d s of guanfacine were 19.9 and 344 n m , respectively. 2 Binding constants of 26 compounds for the two rat cerebral cortex α 2 ‐adrenoceptor subtypes were determined by simultaneous computer modelling of control and guanfacine‐masked drug competition curves as well as plain guanfacine competition curves using [ 3 H]‐MK912 as labelled ligand (i.e. a ‘3‐curve assay’). Of the tested drugs WB4101, corynanthine, rauwolscine, yohimbine, ARC 239 and prazosin were found to be clearly α 2C ‐selective with selectivities ranging from 16 to 30 fold whereas guanfacine, oxymetazoline, BRL 44408 and BRL 41992 were found to be α 2A ‐selective with selectivities ranging from 9 to 22 fold. 3 The K d s of compounds obtained for the cerebral cortex α 2C ‐adrenoceptors showed an almost 1:1 correlation with the corresponding K d s for α 2 ‐adrenoceptors expressed by the pA2d‐gene (the rat ‘α 2 ‐C4’ adrenoceptor) in CHO‐cells. The cerebral cortex α 2A ‐adrenoceptors did not correlate well with the pA2d α 2 ‐adrenoceptor K d s. 4 In the rat spinal cord [ 3 H]‐MK 912 bound to α 2A ‐ and α 2C ‐adrenoceptor sites with similar affinities as in the cerebral cortex and with densities 172 and 7.4 fmol mg −1 protein, respectively. Drug affinities for some compounds showing major selectivity for α 2A ‐ and α 2C ‐adrenoceptors were fully compatible with the notion that the spinal cord sites were α 2A ‐ and α 2C ‐adrenoceptors.