Assessment of the intraocular pressure-lowering activity of bicyclic derivatives of 1-substituted benzyloctahydroisoquinoline

In our study of IOP-lowering agents, we have synthesized several bicyclic a nalogs of 1-benzyloctahydroisoquinoline. The target molecules were synthesi zed in an eleven-step process. Structures were proved through spectrometry, elemental analysis and, in selected cases, high resolution mass spectromet ry. The final products were secondary or tertiary amines containing a 1-ben zyl moiety substituted at the p-position with a methoxy, methyl or chloro g roup. All target molecules were analyzed in 1% solution in distilled water in normotensive rabbits. After topical administration, IOP was monitored in both eyes for up to seven hours. The 1-p-methoxybenzyl molecule 2 was the most active, and caused a maximal IOP drop of 8.8 +/- 1.9 (n = 7) mm Hg in the ipsilateral eye at 4 hours post-administration, with only partial recov ery at seven hours. All other compounds tested either showed very weak acti vity (3-6) or were inactive (1). All compounds produced a contralateral eff ect, and 5 induced rebound ocular hypertension. We conclude that selected t ertiary bicyclic 1-p-methoxybenzyl-octahydroisoquinolines, particularly N-m ethylated structures, exhibit a significant IOP-lowering effect in normoten sive rabbits.