Premium
[ 3 H]‐idazoxan binding to rabbit cerebral cortex recognises multiple imidazoline I 2 ‐type receptors: pharmacological characterization and relationship to monoamine oxidase
Author(s) -
Renouard Anne,
Widdowson Peter S.,
Cordi Alex
Publication year - 1993
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.1476-5381.1993.tb13618.x
Subject(s) - idazoxan , imidazoline receptor , rauwolscine , rilmenidine , chemistry , prazosin , endocrinology , guanabenz , medicine , yohimbine , binding site , receptor , agonist , biology , antagonist , biochemistry
1 In rabbit cerebral cortical homogenates, saturation analysis of [ 3 H]‐idazoxan, an α 2 ‐adrenoceptor antagonist, revealed high affinity binding to a single site with high density. Competition experiments demonstrated that the [ 3 H]‐idazoxan recognition site was insensitive to the catecholamines, adrenaline and noradrenaline and possessed a low affinity for the α 2 ‐ and α 1 ‐adrenoceptor antagonists, rauwolscine, yohimbine and prazosin, suggesting that the site was not an adrenoceptor. Mapping [ 3 H]‐idazoxan binding sites in the forebrain of rabbits by autoradiography, showed high densities of I 2 sites in the medial preoptic area and in the stria terminalis. Moderate binding was found in caudate nucleus, putamen, cerebral cortex and hippocampus. 2 The imidazolines cirazoline, naphazoline, guanabenz and BRL44408 along with amiloride, which is structurally related to the imidazolines, all had high affinity for the [ 3 H]‐idazoxan site, suggesting that the site was related to the I 2 imidazoline‐recognition site described by other groups. However, the imidazolines, clonidine and UK‐14,304 and the structurally related rilmenidine all had a low affinity for the binding site, showing that [ 3 H]‐idazoxan was not binding to the I 1 imidazoline‐recognition site found in rat, bovine and human medulla oblongata. 3 Naphazoline, guanabenz, clonidine and amiloride competition studies had Hill slopes which were significantly different from unity ( P < 0.01) and computer analysis showed that the [ 3 H]‐idazoxan binding data could be best fitted to a model which considers binding to two sites ( P < 0.01). One site has a high affinity for idazoxan, cirazoline, naphazoline, guanabenz and amiloride and a moderate affinity for BRL44408 and clonidine (70% of binding) and the second site (30% of binding) has a high affinity for idazoxan and cirazoline, but a lower affinity for naphazoline, guanabenz, amiloride, BRL44408 and clonidine. 4 Experiments using [ 3 H]‐RX821002, in contrast to [ 3 H]‐idazoxan, clearly demonstrated the presence of a single type of α 2 ‐adrenoceptor in rabbit cortex with a pharmacological profile which is similar to the α 2A ‐adrenoceptor possessing a high affinity for yohimbine, rauwolscine, BRL44408 and oxymetazoline, but a lower affinity for prazosin. 5 The monoamine oxidase inhibitors, clorgyline, pargyline and deprenyl had at least a ten fold lower affinity at the rabbirt cortex I 2 site as compared to their known affinity at monoamine oxidase suggesting that the I 2 site is not related to the active site of the enzyme, monoamine oxidase. In addition, the peripheral benzodiazepine ligands, PK‐11195 or Ro 5–4864 both had very low affinities at the I 2 site in rabbit cortex suggesting that the [ 3 H]‐idazoxan binding was not to the peripheral benzodiazepine binding site.