Effects of topical alpha-substituted anandamides on intraocular pressure in normotensive rabbits

Pharm Res. 1997 Dec;14(12):1738-43. doi: 10.1023/a:1012131929940.


Purpose: Anandamides have been observed to lower intraocular pressure in the rabbit eye, preceded by a period of hypertension. Amidases are thought to catabolize these compounds into their component parts, including arachidonic acid. Direct application of arachidonic acid has been observed to cause a marked rise of intraocular pressure. Thus, anandamide analogs resistant to catabolism were thought possibly devoid of this initial hypertension, and their effects on rabbit IOP investigated.

Methods: A series of chiral alpha-substituted anandamides were synthesized and studied for their effect on the intraocular pressure (IOP) of normotensive pigmented rabbits. Each test compound was dissolved in an aqueous 2-hydroxypropyl-beta-cyclodextrin solution (containing 3% polyvinyl alcohol) and administered (62.5 micrograms) unilaterally to the eye.

Results: The most promising compounds caused a statistically significant reduction of IOP (vs. vehicle) in the treated eyes. Of these, the R-alpha-isopropyl compound exhibited the best activity tested. Unlike the alpha-unsubstituted analogs previously studied, hypotensive effects were not preceded by an initial elevation of IOP and indomethacin pre-treatment (12.5 mg, s.c.) did not eliminate the IOP response, as demonstrated by administered R-alpha-isopropyl anandamide.

Conclusions: Catabolism of alpha-unsubstituted anandamides may account for their observed intraocular hypertensive effects. The physiological mechanism by which alpha-substituted anandamides work apparently differs from that of the more easily metabolized alpha-unsubstituted compounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Arachidonic Acids / administration & dosage
  • Arachidonic Acids / pharmacology*
  • Calcium Channel Blockers / administration & dosage
  • Calcium Channel Blockers / pharmacology*
  • Cross-Over Studies
  • Endocannabinoids
  • Female
  • Indomethacin / administration & dosage
  • Indomethacin / pharmacology
  • Intraocular Pressure / drug effects*
  • Male
  • Polyunsaturated Alkamides
  • Rabbits
  • Random Allocation
  • Structure-Activity Relationship


  • Anti-Inflammatory Agents, Non-Steroidal
  • Arachidonic Acids
  • Calcium Channel Blockers
  • Endocannabinoids
  • Polyunsaturated Alkamides
  • R-alpha-isopropyl anandamide
  • anandamide
  • Indomethacin