BICYCLIC DERIVATIVES OF HEXAHYDROAPORPHINE - NOVEL AGENTS THAT LOWER INTRAOCULAR-PRESSURE

We have synthesized a number of novel bicyclic hexahydroaporphines con taining a phenethylamine moiety for preliminary study as intraocular p ressure lowering agents. The target molecules were synthesized in a tw elve step process. The final products were secondary or tertiary amine s containing either an aromatic methoxy or phenolic substituent. These molecules, in hydrochloride salt form, were assayed in doses ranging from 0.1-1.5%. All products and vehicle were administered topically to one eye of normotensive rabbits and intraocular pressure was measured in both eyes for up to six hours. Four of the five compounds examined produced a significant and, in some cases, prolonged, ocular hypotens ive response. Secondary and N-methylated tertiary amines were equally effective, as were compounds containing either the 10-methoxy group or free phenol. Studies are currently in progress to optimize potency an d identify functional and molecular mechanisms of action.