May 1988
Volume 29, Issue 5
Free
Articles  |   May 1988
L-653,328: an ocular hypotensive agent with modest beta receptor blocking activity.
Author Affiliations
  • M F Sugrue
    Centre de Recherche, Merck Sharp and Dohme-Chibret, Riom, France.
  • P Gautheron
    Centre de Recherche, Merck Sharp and Dohme-Chibret, Riom, France.
  • J Grove
    Centre de Recherche, Merck Sharp and Dohme-Chibret, Riom, France.
  • P Mallorga
    Centre de Recherche, Merck Sharp and Dohme-Chibret, Riom, France.
  • M P Viader
    Centre de Recherche, Merck Sharp and Dohme-Chibret, Riom, France.
  • J J Baldwin
    Centre de Recherche, Merck Sharp and Dohme-Chibret, Riom, France.
  • G S Ponticello
    Centre de Recherche, Merck Sharp and Dohme-Chibret, Riom, France.
  • S L Varga
    Centre de Recherche, Merck Sharp and Dohme-Chibret, Riom, France.
Investigative Ophthalmology & Visual Science May 1988, Vol.29, 776-784. doi:
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    • Get Citation

      M F Sugrue, P Gautheron, J Grove, P Mallorga, M P Viader, J J Baldwin, G S Ponticello, S L Varga; L-653,328: an ocular hypotensive agent with modest beta receptor blocking activity.. Invest. Ophthalmol. Vis. Sci. 1988;29(5):776-784.

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      © ARVO (1962-2015); The Authors (2016-present)

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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)

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