title: Discrimination and pharmacological characterization of I2-imidazoline sites with [3H]idazoxan and alpha-2 adrenoceptors with [3H]RX821002 (2-methoxy idazoxan) in the human and rat brains.
abstract: The alpha-2 adrenoceptor antagonist idazoxan has been shown to also recognize with high affinity nonadrenoceptor sites (I2-imidazoline sites). In contrast, the 2-methoxy derivative of idazoxan, 2-methoxy idazoxan (RX821002), binds almost exclusively to alpha-2 adrenoceptors. The purpose of this study was to assess and extend the pharmacological characterization of I2-imidazoline sites and alpha-2 adrenoceptors in the human and rat brains. Competition studies with several imidazoli(di)ne/guanidine drugs and other nonrelated structures were performed in cortical membranes against [3H]idazoxan (4 nM in the presence of 10(-6) M I-epinephrine to prevent binding to alpha-2 adrenoceptors) or [3H]RX821002 (1 nM). Drugs such as cirazoline, guanoxan, naphazoline, tolazoline, clonidine, bromoxidine (UK 14,304) and phenylbiguanide displaced [3H]idazoxan from two distinct binding sites, which suggested the existence of two affinity states for I2-imidazoline sites that were not modulated by MgCl2 or the nucleotide analog guanylyl-5'-imido-diphosphate. Binding affinities at the low-affinity site (KiL) were consistently more than 2 orders of magnitude lower than binding affinities at the high-affinity site (KiH), and there was a good correlation between KiH and KiL values for a given drug in the human (r = 0.89) and rat (r = 0.92) brains. For 18 to 22 drugs, the Ki values in the human brain correlated well with the corresponding Ki values in the rat brain both for I2-imidazoline sites (r = 0.94) and alpha-2 adrenoceptors (r = 0.97). However, the Ki values for I2-imidazoline sites did not correlate with the Ki values for alpha-2 adrenoceptors in human and rat brains. The order of drug potency for the I2-imidazoline sites was: guanoxan (1.3 nM) approximately cirazoline > idazoxan approximately naphazoline > clonidine > phentolamine > RX821002 > (8aR, 12aS, 13aS)-3-methoxy-12-methanesulfonyl-5,6,8a,9,10,11,12,12a,13,13a- decahydro-8H-isoquino[2,1-g]-naphthyridine (RS 15385-197) (> 10 microM). In contrast, the potencies at the alpha-2 adrenoceptor were: RS 1538-197 (0.3 nM) > RX821002 > clonidine > phentolamine > idazoxan approximately naphazoline > guanoxan approximately cirazoline (307 nM). The results demonstrate that I2-imidazoline sites (labeled by [3H]idazoxan) and alpha-2 adrenoceptors are different pharmacological entities with similar characteristics in the human and rat brains. In both species, I2-imidazoline sites are markedly heterogeneous in nature.
authors.affiliation: Department of Fundamental Biology and Health Sciences, University of the Balearic Islands, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Miralles
authors.forename: G
authors.initials: G
authors.lastname: Olmos
authors.forename: M
authors.initials: M
authors.lastname: Sastre
authors.forename: F
authors.initials: F
authors.lastname: Barturen
authors.forename: I
authors.initials: I
authors.lastname: Martin
authors.forename: J A
authors.initials: JA
authors.lastname: Garcia-Sevilla
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000378:metabolism*; D000328:Adult; D000818:Animals; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry; D004146:Dioxanes / Q000378:metabolism*; D004837:Epinephrine / Q000494:pharmacology; D005260:Female; D006801:Humans; D019329:Idazoxan / Q000031:analogs & derivatives; D054755:Imidazoline Receptors; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000032:analysis / Q000187:drug effects / Q000378:metabolism*; D011955:Receptors, Drug / Q000032:analysis / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D054755:Imidazoline Receptors; D011942:Receptors, Adrenergic, alpha; D011955:Receptors, Drug; C058525:2-methoxyidazoxan; D019329:Idazoxan; D004837:Epinephrine