ABSTRACT
Recent studies have suggested that alpha(2)-adrenergic agonists prevent neuronal cell death in a number of animal models, although the mechanism of alpha(2)-neuroprotection remains unclear. In a retinal ischemia model, the alpha(2)-specific agonist brimonidine (1 mg/kg i.p.) preserves approximately 80% of the electroretinogram (ERG) b-wave. The protective effect of brimonidine is completely blocked by coadministration of the alpha(2)- antagonist rauwolscine. Brimonidine treatment preserves the ERG b-wave if animals are treated 1 or 3 h before ischemia, but has no effect if it is injected during ischemia. The 3-h pretreatment effect is blocked by i.v. injection of rauwolscine 2 h later (1 h before ischemia). A comparison of vitreous humor glutamate levels between untreated and brimonidine-treated eyes shows that 1) after ischemia, glutamate levels rise 2- to 3-fold in the untreated animals, and 2) glutamate levels in the brimonidine-treated animals are comparable to the nonischemic controls. Hence, the mechanism for brimonidine-mediated protection in the retinal ischemia model requires activation of the alpha(2)-adrenergic receptors immediately before and during ischemia. These data suggest that activation of the alpha(2)-adrenergic receptor may reduce ischemic retinal injury by preventing the accumulation of extracellular glutamate and aspartate.
Subject(s)
Adrenergic alpha-2 Receptor Agonists , Adrenergic alpha-Agonists/therapeutic use , Aspartic Acid/metabolism , Glutamic Acid/metabolism , Ischemia/prevention & control , Quinoxalines/therapeutic use , Retina/physiopathology , Retinal Vessels/physiopathology , Vitreous Body/metabolism , Adrenergic alpha-Antagonists/pharmacology , Animals , Brimonidine Tartrate , Chromatography, Liquid , Electroretinography , Extracellular Space/metabolism , Ischemia/pathology , Ischemia/physiopathology , Male , Mass Spectrometry , Rats , Rats, Inbred BN , Retina/drug effects , Retina/pathology , Retinal Ganglion Cells/drug effects , Retinal Ganglion Cells/metabolism , Retinal Vessels/drug effects , Vitreous Body/drug effects , Vitreous Body/pathology , Yohimbine/pharmacologyABSTRACT
A series of 2-(arylamino)imidazoles was synthesized and evaluated for activity at alpha 1- and alpha 2-adrenoceptors. This class of agents has been shown to have potent and selective agonist activity at the alpha 2-adrenoceptors. The most potent member of this class, 2-[(5-methyl-1,4-benzodioxan-6yl)amino]imidazole, proved efficacious for the reduction of intraocular pressure upon topical administration and for the reduction of blood pressure upon intravenous administration. During the course of our studies, we developed a new reagent that allowed rapid assembly of the target compounds. This reagent, N-(2,2-diethoxyethyl)carbodiimide, was convenient to prepare and was stable under low-temperature storage conditions.
Subject(s)
Adrenergic alpha-2 Receptor Agonists , Imidazoles/chemistry , Animals , Blood-Brain Barrier/drug effects , Brimonidine Tartrate , Imidazoles/pharmacology , Intraocular Pressure/drug effects , Macaca fascicularis , Quinoxalines/chemistry , Quinoxalines/pharmacology , RabbitsABSTRACT
We have synthesized 2-[(5-methylbenz-1-ox-4-azin-6-yl)imidazoline, 3, a potent, peripherally acting alpha 2 adrenoceptor agonist. The agent is conveniently prepared in five steps from 2-amino-m-cresol. The agent has demonstrated good selectivity for alpha 2 adrenoceptors in binding and functional studies. When applied topically to eyes, the agent is efficacious for the reduction of intraocular pressure. The agent does not penetrate the blood-brain barrier and, as a consequence, does not lower blood pressure or induce sedation when administered topically or intravenously. We have determined the pKa and log P in water versus both octanol and dodecane of 3 and a set of related agents. The best physical parameter to explain its lack of central nervous system penetration appears to be log P measured in octanol versus water.
