title: Mechanisms of adrenergic agonist induced allergy bioactivation and antigen formation.
abstract: Reduction of elevated intraocular pressure with alpha 2 agonists has proved to be an exciting new therapeutic approach for the treatment of glaucoma. We have studied the chemical reactivities of several alpha 2 agonists and known allergens to elucidate the origin of the observed ocular allergic response to the alpha 2 agonist apraclonidine. The oxidation potentials of clonidine, apraclonidine, brimonidine, and two known allergens, amodiaquine, and epinephrine, were measured vs. a standard calomel electrode.. Agents that were oxidatively labile were treated with both chemical and enzymatic oxidants. Clonidine and brimonidine proved to be oxidatively stable in sharp contrast to apraclonidine which had an oxidation potential similar to that observed with epinephrine and amodiaquine, two known allergy-inducing agents. In addition, two glutathione-apraclonidine conjugates formed by the in-situ reaction of glutathione with an enzymatically oxidized apraclonidine intermediate were isolated and their structures determined using spectroscopic methods. The structures were shown to be analogous to those obtained with amodiaquine and epinephrine. Apraclonidine, like amodiaquine and epinephrine, possesses a hydroquinone-like subunit and can be readily oxidized and conjugated with thiols modeling well known hapten-forming reactions. Brimonidine, like clonidine, lacks the hydroquinone subunit and does not undergo the thiol conjugation reactions.
authors.affiliation: Department of Chemistry, University of Virginia Charlottesville, VA 22901, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Thompson
authors.forename: T L
authors.initials: TL
authors.lastname: Macdonald
authors.forename: M E
authors.initials: ME
authors.lastname: Garst
authors.forename: A
authors.initials: A
authors.lastname: Wiese
authors.forename: S A
authors.initials: SA
authors.lastname: Munk
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000737:chemistry*; D000485:Allergens / Q000737:chemistry*; D000655:Amodiaquine / Q000737:chemistry; D000068438:Brimonidine Tartrate; D003000:Clonidine / Q000031:analogs & derivatives / Q000737:chemistry; D004837:Epinephrine / Q000737:chemistry; D005978:Glutathione / Q000737:chemistry; D006735:Horseradish Peroxidase / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D010084:Oxidation-Reduction; D011810:Quinoxalines / Q000737:chemistry
chemical_list: D000316:Adrenergic alpha-Agonists; D000485:Allergens; D011810:Quinoxalines; D000655:Amodiaquine; D000068438:Brimonidine Tartrate; C016986:apraclonidine; D006735:Horseradish Peroxidase; D005978:Glutathione; D003000:Clonidine; D004837:Epinephrine