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R-Enantiomer of timolol: a potential selective ocular antihypertensive agent

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Abstract

Various studies were conducted to evaluate the effects of timolol, an S-enantiomer, relative to its R-enantiomer upon intraocular pressure and related ocular systems in the rabbit. The R-enantiomer was about one-third as potent as timolol in displacing3H-dihydroalprenolol binding to iris-ciliary body tissue, reducing aqueous humor formation, and lowering intraocular pressure of α-chymotrypsin hypertensive eyes. In contrast, the R-enantiomer was 50 to 90 times less potent than timolol in antagonizing the effects of isoproterenol on pulmonary and atrial β-adrenergic receptors. The data indicate that the R-enantiomer may lower intraocular pressure in man at concentrations less likely than timolol to block extraocular β-adrenergic receptors. Finally, to account for the differential effect of the R-enantiomer upon ocular as opposed to extraocular β-adrenergic receptors, it is tentatively suggested that this agent may also act upon a population of ocular β-adrenergic receptors showing relatively poor stereoselectively.

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References

  • Adler-Graschinsky E, Langer SZ (1975) Possible role of a β-adrenoceptor in the regulation of noreadrenaline release by nerve stimulation through a positive feed-back mechanism. Br J Pharmacol 53:43–50

    PubMed  Google Scholar 

  • Barrett AM, Nunn B (1970) Adrenergic neuron blocking properties of (±)-propranolol and (+)-propranolol. J Pharm Pharmacol 22:806–810

    PubMed  Google Scholar 

  • Bromberg BB, Gregory DS, Sears ML (1980) β-Adrenergic receptors in ciliary processes of the rabbit. Invest Ophthalmol Vis Sci 19:203–207

    PubMed  Google Scholar 

  • Cepelik J, Cernohorsky M (1981) The effects of adrenergic agonists and antagonists on the adenylate cyclase in albino rabbit ciliary processes. Exp Eye Res 32:291–299

    Article  PubMed  Google Scholar 

  • Chiou GCY (1983) Effects of D-timolol on intraocular pressure, heart rate, cardiac contractility and tracheal muscle function. Current Eye Res 2:507–510

    Google Scholar 

  • Dafna Z, Lahav M, Melamed E (1979) Localization of β-adrenoceptors in the anterior segment of the albino rabbit eye using a fluorescent analog of propranolol. Exp Eye Res 29: 327–330

    Article  PubMed  Google Scholar 

  • Dahlof C, Ablad B, Borg KO, Ek L, Waldeck B (1975) Prejunctional inhibition of adrenergic nervous vasomotor control due to β-receptor blockade. In: Almgren O, Carlsson A, Engel J (eds) Chemical tools in catecholamine research. II. Regulation of catecholamine turnover. North-Holland/American Elsevier, New York, pp 201–210

    Google Scholar 

  • Day MD, Owen DAA, Warren PR (1968) An adrenergic neuron blocking action of propranolol in isolated tissues. J Pharm Pharmacol 20:130S–134S

    Google Scholar 

  • Dean RB, Dixon WJ (1951) Simplified statistics for small numbers of observations. Anal Chem 23:636–638

    Article  Google Scholar 

  • Dunnett CW (1964) New tables for multiple comparisons with a control. Biometrics 20: 482–491

    Google Scholar 

  • Eliash S, Weinstock M (1971) Role of adrenergic neurone blockade in the hypotensive action of propranolol. Br J Pharmacol 43:287–294

    PubMed  Google Scholar 

  • Guimaraes S, Brando F, Paira MQ (1978) A study of the adrenoceptor-mediated feedback mechanisms by using adrenaline as a false transmitter. Naunyn Schmiedebergs Arch Pharmacol 305: 185–188

    Article  PubMed  Google Scholar 

  • Harms HH (1976) Isoproterenol antagonism of caudioselective β-adrenergic receptor blocking agents: a comparative study of human and guinea-pig cardiac and bronchial β-adrenergic receptors. J Pharmacol Exp Ther 199:329–335

    PubMed  Google Scholar 

  • Langer SZ, Enero MA, Adler-Graschinsky E, Dubocovich ML, Celuchi SM (1975) Presynaptic regulatory mechanisms for noradrenaline release by nerve stimulation. In: Davies DS, Reid JL (eds) Central actions of drugs in blood pressure regulation. University Park Press, Baltimore, pp 133–150

    Google Scholar 

  • Langer SZ, Cavero I, Massingham R (1980) Recent developments in nor-adrenergic neurotransmission and its relevance to the mechanism of action of certain antihypertensive agents. Hypertension 2:372–382

    PubMed  Google Scholar 

  • Liu HK, Chiou GCY (1981) Continuous, simultaneous and instant display of aqueous humor dynamics with a micro-spectrophotometer and a sensitive drop counter. Exp Eye Res 32:583–592

    PubMed  Google Scholar 

  • Liu JHK, Bartels SP, Neufeld AH (1983) Effects of 1- and d-timolol on cyclic AMP synthesis and intraocular pressure in water-loaded, albino and pigmented rabbits. Invest Ophthalmol Vis Sci 24:1276–1282

    PubMed  Google Scholar 

  • Ljung B, Abland B, Dahlof C, Henning M, Hultberg E (1975) Impaired vasoconstrictor nerve function in spontaneously hypertensive rats after long-term treatment with propranolol and metroprolol. Blood Ves 12:311–315

    Google Scholar 

  • Lowry OH, Rosenbrough NH, Farr AL, Fandall R (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275

    PubMed  Google Scholar 

  • Mylecharane EJ, Raper C (1973) Further studies on the adrenergic neuron blocking activity of some β-adrenoceptor antagonists and guanethidine. J Pharm Pharmacol 25:213–220

    PubMed  Google Scholar 

  • Nathanson JA (1980) Adrenergic regulation of intraocular pressure: identification of β2-adrenergic-stimulated adenylate cyclase in ciliary process epithelium. Proc Natl Acad Sci 77: 7420–7424

    PubMed  Google Scholar 

  • Neufeld AH, Page ED (1977) In vitro determination of the ability of drugs to bind to adrenergic receptors. Invest Ophthalmol Vis Sci 16:1118–1124

    PubMed  Google Scholar 

  • Schild HO (1947) pA2, a new scale for the measurement of drug antagonism. Br J Pharmacol 2:189–206

    Google Scholar 

  • Sears D, Sears M (1974) Blood-aqueous barrier and -chymotrypsin glaucoma in rabbits. Am J Ophthalmol 77:378–383

    PubMed  Google Scholar 

  • Vale J, Phillips CI (1970) Effect ofdl- andd-propranolol on ocular tension in rabbits and patients. Exp Eye Res 9:82–90

    PubMed  Google Scholar 

  • Vareilles P, Lotti VJ (1981) Effects of timolol on aqueous humor dynamics in the rabbit. Ophthalmic Res 13:72–79

    Google Scholar 

  • Vareilles P, Conquet Ph, LeDouarec JC (1977a) A method for the routine intraocular pressure (IOP) measurement in the rabbit: range of IOP variations in this species. Exp Eye Res 24: 369–375

    Article  PubMed  Google Scholar 

  • Vareilles P, Silverstone D, Plazonnet B, LeDouarec JC, Sears M, Stone CA (1977b) Comparison of the effects of timolol and other adrenergic agents on intraocular pressure in the rabbit. Invest Ophthalmol Vis Sci 16:987–996

    PubMed  Google Scholar 

  • Vareilles P, Durand G, Siou G, LeDouarec JC (1979) Le modele de glaucome experimental a l'alpha-chymotrypsin chez le lapin: Etude histologique. J Fr Ophthalmol 2:561–568

    Google Scholar 

  • Zimmerman TJ, Boger WP III (1979) The β-adrenergic blocking agents and the treatment of glaucoma. Surv Ophthalmol 23:347–362

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Merck Institute for Therapeutic Research, Merck Sharp & Dohme Research Laboratories, 19486, West Point, PA, USA

    Norman N. Share, Victor J. Lotti, Dennis M. Gross & Clement A. Stone

  2. Merck Sharp & Dohme Chibret Research Center, Riom, France

    Pierre Gautheron & Claude Schmitt

  3. Merck Frosst Laboratories, Kirkland, Canada

    Ronald A. Hall

Authors
  1. Norman N. Share
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  2. Victor J. Lotti
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  3. Pierre Gautheron
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  4. Claude Schmitt
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  5. Dennis M. Gross
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  6. Ronald A. Hall
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  7. Clement A. Stone
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Share, N.N., Lotti, V.J., Gautheron, P. et al. R-Enantiomer of timolol: a potential selective ocular antihypertensive agent. Graefe's Arch Clin Exp Ophthalmol 221, 234–238 (1984). https://doi.org/10.1007/BF02134145

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  • DOI: https://doi.org/10.1007/BF02134145

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