Synthesis and intraocular pressure-lowering activity of bicyclic octahydroisoquinolines

Victoria F. Roche, S. E. Ohia, S. L. Saha, I. N. Igbo, J. Taniyama, Catherine A. Opere

Research output: Contribution to journalArticle

Abstract

Purpose: In our continuing study of bicyclic phenethylamine-based IOP-lowering agents, bicyclic 1-(p-substitued) benzylocta-hydroisoquinolines (ISOQs) have been synthesized and analyzed in normotensive rabbits. Methods: The target molecules were synthesized in an eleven step process. Key intermediates were purified chromatographically and structure proved through standard spectroscopic techniques. The ISOQs were secondary (N-H) or tertiary amines (N-CH3 or N-p-methoxybenzyl) with either a p-Cl, CH3 or OCH3 substituent on the 1-benzyl moiety. All compounds were analyzed in salt form at a concentration of 1.0% in distilled water. After topical administration of drug or vehicle into one normotensive eye, IOP was monitored in both eyes for up to seven hours with an Alcon pneumatonometer. The activity of the ISOQs was compared to 1% epinephrine. Results: Initial studies with N-CH3 analogs in 5 rabbits showed the p-OCH3 analog (1) to be the most promising. Compound 1 caused a maximal IOP drop of 6.3 ± 2.1 mm Hg in the ipsilateral eye with only partial recovery at seven hours. The N-(p-methoxybenzyl) p-OCH3 derivative 3 produced a maximal IOP drop of 4.3 ± 1.2 mm Hg with essentially complete recovery by six hours. A significant contralateral effect was noted with both tertiary amines. Surprisingly, the secondary amine (proven highly active in the bicyclic hexahydroaporphine molecular series) was inactive in the ISOQ series. Conclusions: Tertiary, but not secondary, bicyclic ISOQs exhibited a significant IOP lowering effect in normotensive rabbits. A p-OCH3 substituent provided a more potent sustained IOP lowering effect than the p-CI or CH3 moiety.

Original languageEnglish
JournalInvestigative Ophthalmology and Visual Science
Volume37
Issue number3
StatePublished - Feb 15 1996

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Intraocular Pressure
Amines
Rabbits
Topical Administration
Epinephrine
Salts
Water

All Science Journal Classification (ASJC) codes

  • Ophthalmology

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Synthesis and intraocular pressure-lowering activity of bicyclic octahydroisoquinolines. / Roche, Victoria F.; Ohia, S. E.; Saha, S. L.; Igbo, I. N.; Taniyama, J.; Opere, Catherine A.

In: Investigative Ophthalmology and Visual Science, Vol. 37, No. 3, 15.02.1996.

Research output: Contribution to journalArticle

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abstract = "Purpose: In our continuing study of bicyclic phenethylamine-based IOP-lowering agents, bicyclic 1-(p-substitued) benzylocta-hydroisoquinolines (ISOQs) have been synthesized and analyzed in normotensive rabbits. Methods: The target molecules were synthesized in an eleven step process. Key intermediates were purified chromatographically and structure proved through standard spectroscopic techniques. The ISOQs were secondary (N-H) or tertiary amines (N-CH3 or N-p-methoxybenzyl) with either a p-Cl, CH3 or OCH3 substituent on the 1-benzyl moiety. All compounds were analyzed in salt form at a concentration of 1.0{\%} in distilled water. After topical administration of drug or vehicle into one normotensive eye, IOP was monitored in both eyes for up to seven hours with an Alcon pneumatonometer. The activity of the ISOQs was compared to 1{\%} epinephrine. Results: Initial studies with N-CH3 analogs in 5 rabbits showed the p-OCH3 analog (1) to be the most promising. Compound 1 caused a maximal IOP drop of 6.3 ± 2.1 mm Hg in the ipsilateral eye with only partial recovery at seven hours. The N-(p-methoxybenzyl) p-OCH3 derivative 3 produced a maximal IOP drop of 4.3 ± 1.2 mm Hg with essentially complete recovery by six hours. A significant contralateral effect was noted with both tertiary amines. Surprisingly, the secondary amine (proven highly active in the bicyclic hexahydroaporphine molecular series) was inactive in the ISOQ series. Conclusions: Tertiary, but not secondary, bicyclic ISOQs exhibited a significant IOP lowering effect in normotensive rabbits. A p-OCH3 substituent provided a more potent sustained IOP lowering effect than the p-CI or CH3 moiety.",
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AU - Taniyama, J.

AU - Opere, Catherine A.

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