title: Beta-adrenoceptor antagonist activities and binding affinities of timolol enantiomers in rat atria.
abstract: S-Timolol is an effective anti-glaucoma drug, but has potentially hazardous side effects. Recently, R-timolol, also, has been reported to be effective in lowering elevated intraocular pressure. In the present study, the beta-adrenoceptor antagonist activities and binding of R- and S-enantiomers of timolol have been examined on rat atrial preparations. The beta-antagonistic activities were investigated using spontaneously beating rat heart atria. Both timolol enantiomers inhibited (-)-isoprenaline-induced chronotropic action competitively. S-Timolol was about 54 times more potent than R-timolol. The apparent binding affinities of timolol enantiomers to beta 1- and beta 2-adrenoceptors were determined by a radioligand binding assay using (-)-[125I]iodocyanopindolol (ICYP) as a marker and CGP 20712 A as a beta 1- and ICI 118,551 as a beta 2-adrenoceptor antagonist. Both enantiomers of timolol inhibited ICYP binding in nanomolar concentrations with Hill coefficients near unity. Neither enantiomer showed selectivity between beta 1- and beta 2-adrenoceptors, but R-timolol was approximately 30 times less active than S-timolol. It is concluded that R-timolol is a relatively potent non-selective beta-adrenoceptor blocking agent, but may possibly exert a more localized beta-adrenoceptor action in the eye than S-timolol, thus improving the safety of ocular timolol therapy.
authors.affiliation: Department of Pharmacology, University of Turku, Finland.
authors.forename: S
authors.initials: S
authors.lastname: Karhuvaara
authors.forename: T
authors.initials: T
authors.lastname: Kaila
authors.forename: R
authors.initials: R
authors.lastname: Huupponen
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D020120:Iodocyanopindolol; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010869:Pindolol / Q000031:analogs & derivatives; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013999:Timolol / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000319:Adrenergic beta-Antagonists; D007457:Iodine Radioisotopes; D013999:Timolol; D020120:Iodocyanopindolol; D010869:Pindolol