title: Beta-adrenoceptor binding potencies of new aliphatic and alicyclic oxime ethers and their relevance to intraocular pressure control.
abstract: The selectivity and binding potency of a series of alkyliminoxypropanolamines characterized by the lack of an aromatic nucleus are studied using a new non-selective radioligand, (-)-(125I)-Iodocyanopindolol. The relationship between the effectiveness in lowering the intraocular pressure (IOP) in experimental hypertensive rabbit eyes and their capacity to bind to ciliary processes beta 2-adrenoceptors is discussed. The inhibition constant (Ki) and beta 2/beta 1 ratios indicate a beta 2-selectivity for the tested drugs. Cyclopropyl, dicyclopropyl, cyclopentyl and cyclohexyl derivatives displayed a potent binding to ciliary processes beta 2-adrenoceptors and lowered the IOP about -18%. These compounds induced a lowering in IOP equal to that produced by timolol and appear to be effective and safe beta-adrenergic antagonists in open-angle glaucoma therapy. Decreasing the size of the alkyl group of the oxime, removing the oxime function or modifying the beta-hydroxyl group from the side chain led to a significant decrease in beta 2-adrenoceptor binding and induced weak hypotensive ocular activity. Since the tested alkyliminoxypropanolamine series has very similar physicochemical characteristics and therefore, ruled out the differences in their ability to reach, through the cornea, the targeted ciliary processes, it was demonstrated that contrary to generally held views, the action of the new beta-antagonist series on IOP is related to their ability to antagonize ocular beta 2-adrenoceptors.
authors.affiliation: Alcon Research and Development, Kaysersberg, France.
authors.forename: J
authors.initials: J
authors.lastname: Himber
authors.forename: J
authors.initials: J
authors.lastname: Velly
authors.forename: P
authors.initials: P
authors.lastname: Kintz
authors.forename: G
authors.initials: G
authors.lastname: de Burlet
authors.forename: G
authors.initials: G
authors.lastname: Andermann
authors.forename: G
authors.initials: G
authors.lastname: Leclerc
mesh_terms: D000818:Animals; D002923:Cilia / Q000378:metabolism; D005260:Female; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007429:Intraocular Pressure / Q000187:drug effects*; D007457:Iodine Radioisotopes; D020120:Iodocyanopindolol; D008168:Lung / Q000378:metabolism; D008297:Male; D008566:Membranes / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D010091:Oximes / Q000378:metabolism* / Q000494:pharmacology; D010869:Pindolol / Q000031:analogs & derivatives; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
chemical_list: D007457:Iodine Radioisotopes; D010091:Oximes; D011943:Receptors, Adrenergic, beta; D020120:Iodocyanopindolol; D010869:Pindolol