title: L-653,328: an ocular hypotensive agent with modest beta receptor blocking activity.
abstract: L-653,328 is the acetate ester of L-652,698 ((S)-3-tert-butylamino-1-[4-[2(hydroxy)ethyl]phenoxy]2-propanol). The penetration of L-652,698 into the albino rabbit eye was enhanced when the compound was instilled as its prodrug acetate ester. The instillation (one drop of 50 microliter) of 0.01, 0.05 and 0.1% solutions of L-653,328 significantly decreased in a dose-dependent manner the elevated intraocular pressure (IOP) of alpha-chymotrypsinized rabbits by 3.2, 4.7 and 6.1 mm Hg, respectively. A 0.01% solution of L-652,698 failed to significantly lower IOP, whereas this dose of timolol (3.8 mm Hg) and betaxolol (3.3 mm Hg) was effective. L-652,698 was active at 0.05% and 0.1%. Extraocular beta-adrenoceptor blockade was quantified in ganglion-blocked, conscious rabbits by determining effects on heart rate and blood pressure changes to i.v. isoproterenol (0.5 microgram/kg). Doses of timolol blocking isoproterenol-induced hypotension and tachycardia by 50% were 0.0065% and 0.03%, respectively. The corresponding doses for betaxolol were greater than 3% (43% inhibition) and 0.3%. Heart rate and blood pressure changes to isoproterenol were blocked by 18 and 36%, respectively, after the instillation of a 3% solution of L-653,328. The reduced propensity of L-653,328 for extraocular beta-adrenoceptor blockade stems from the modest affinity of L-652,698, its active moiety, for beta-adrenoceptors. The Ki values of L-652,698 for displacement of 125I-iodocyanopindolol binding to beta 1-(left ventricle) and beta 2-binding sites (iris + ciliary body) in the rabbit were 5.7 microM and 7.3 microM, respectively. In marked contrast, the corresponding values for timolol were 12 nM and 1.8 nM.(ABSTRACT TRUNCATED AT 250 WORDS)
mesh_terms: D000319:Adrenergic beta-Antagonists; D000818:Animals; D015784:Betaxolol; D002924:Ciliary Body / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007429:Intraocular Pressure / Q000187:drug effects*; D007457:Iodine Radioisotopes; D020120:Iodocyanopindolol; D007498:Iris / Q000378:metabolism; D009883:Ophthalmic Solutions; D010600:Pharmacology; D010869:Pindolol / Q000031:analogs & derivatives / Q000378:metabolism; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D011412:Propanolamines / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D011869:Radioligand Assay; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D013999:Timolol / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000319:Adrenergic beta-Antagonists; D007457:Iodine Radioisotopes; D009883:Ophthalmic Solutions; D011355:Prodrugs; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; C055890:L 653328; D013999:Timolol; D020120:Iodocyanopindolol; D010869:Pindolol; D015784:Betaxolol