title: [3H]idazoxan and some other alpha 2-adrenergic drugs also bind with high affinity to a nonadrenergic site.
abstract: We compared the pharmacological properties of the alpha 2-adrenergic radioligand [3H]idazoxan with those of [3H]rauwolscine in rat and [3H]yohimbine in human renal cortical membranes. The density of "specific" [3H]idazoxan binding sites (defined by 100 microM tolazoline) was twice as high as that of [3H]rauwolscine in rat kidney and four times as high as that of [3H]yohimbine in human kidney. A variety of structurally different drugs fully competed for specific [3H]rauwolscine and [3H]yohimbine binding, with affinities appropriate for the interaction with alpha 2-adrenergic receptors. Specific [3H]idazoxan binding, however, was only partially competed for by the catecholamines epinephrine and norepinephrine in both tissues. Thus, [3H]idazoxan labels both alpha 2-adrenergic receptors and a nonadrenergic site. Clonidine, B-HT 920, moxonidine, phentolamine, prazosin, yohimbine, dopamine, and serotonin also could not compete for this site. However, UK 14,304, guanabenz, indanidine, tolazoline, oxymetazoline, and SK&F 104,078 competed for the additional [3H]idazoxan sites with affinities similar to those at alpha 2-adrenergic receptors. [3H]idazoxan binding substantially in excess of [3H]rauwolscine or [3H]yohimbine binding was also found in human platelets, myometrium, and erythroleukemia (HEL) cells but not in three cell lines lacking alpha 2-receptors (MDCK, BC3H1, and Jurkat cells). Although we have been unsuccessful thus far in defining the precise nature of the additional [3H]idazoxan binding sites, we hypothesize that these sites may be closely affiliated with alpha 2-adrenergic receptors but clearly distinct from the catecholamine binding site of the receptor. The results indicate that care must be taken in the use of [3H]idazoxan or drugs that are recognized at its nonadrenergic site when studying alpha 2-adrenergic effects and receptor subtypes.
authors.affiliation: Department of Pharmacology, University of California San Diego, La Jolla 92093.
authors.forename: M C
authors.initials: MC
authors.lastname: Michel
authors.forename: O E
authors.initials: OE
authors.lastname: Brodde
authors.forename: B
authors.initials: B
authors.lastname: Schnepel
authors.forename: J
authors.initials: J
authors.lastname: Behrendt
authors.forename: R
authors.initials: R
authors.lastname: Tschada
authors.forename: H J
authors.initials: HJ
authors.lastname: Motulsky
authors.forename: P A
authors.initials: PA
authors.lastname: Insel
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D004146:Dioxanes / Q000378:metabolism*; D004147:Dioxins / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000494:pharmacology; D006801:Humans; D019329:Idazoxan; D007672:Kidney Cortex / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D012964:Sodium / Q000494:pharmacology; D015016:Yohimbine / Q000378:metabolism
chemical_list: D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D004147:Dioxins; D011942:Receptors, Adrenergic, alpha; D015016:Yohimbine; D006160:Guanosine Triphosphate; D012964:Sodium; D019329:Idazoxan