benzofurans and Ocular-Hypertension

A series of 8-substituted benzodifuran analogs was prepared and evaluated for 5-HT(2A) receptor binding and activation. Several compounds containing ether and ester functionality were found to be potent agonists. Topical ocular administration of 5, 18, and 25 effectively reduced intra-ocular pressure in the hypertensive cynomolgus monkey eye in the range of 25-37%.

Topics: Animals; Antihypertensive Agents; Benzofurans; Macaca fascicularis; Muscle, Smooth, Vascular; Ocular Hypertension; Rats; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Agonists; Serotonin Receptor Agonists; Structure-Activity Relationship

These experiments sought to: (1) determine if alpha 2/I1 agonists that are topically active on the eye have similar effects on intraocular pressure when applied to the CNS and (2) ascertain whether these agents lower IOP, in part, via central alpha 2 receptors and/or imidazoline (I1) receptors. New Zealand White rabbits were fitted with chronic indwelling stainless-steel guide cannulas in several brain regions including the lateral ventricle, third ventricle (3V), or medullary intermediate reticular zone. Animals were allowed 5 days' recovery time prior to experiments measuring the effects of drugs on IOP via applanation pneumatonometry. Some animals were also pretreated with 400 micrograms of 6-hydroxydopamine injected into the lateral ventricle to determine the site of action of these alpha 2/I1 agonists. In initial experiments involving microinjection into the lateral ventricle, UK-14,304-18 evoked ocular hypotension that was inhibited by the alpha 2-antagonist rauwolscine but not by the I1-receptor antagonist efaroxan. Conversely, moxonidine and oxymetazoline were preferentially inhibited by efaroxan rather than by rauwolscine. Subsequently, experiments have shown that moxonidine and oxymetazoline, but not UK-14,304-18 will lower intraocular pressure when microinjected into the medullary intermediate reticular zone region and that efaroxan, but not rauwolscine, will inhibit ocular hypotension induced by moxonidine and oxymetazoline. Pretreatment with 6-hydroxydopamine (48 hours) completely eliminated the ocular hypotension induced by moxonidine. These preliminary data demonstrate that alpha 2- and I1-receptors in the brain mediate ocular hypotension induced by UK-14,304-18 and moxonidine/oxymetazoline, respectively. Moreover, the medullary intermediate reticular zone area of the brain stem is the probable presynaptic site mediating ocular hypotension induced by moxonidine and oxymetazoline.

Topics: Administration, Topical; Animals; Benzofurans; Cornea; Imidazoles; Imidazoline Receptors; Injections, Intraventricular; Intraocular Pressure; Male; Medulla Oblongata; Ocular Hypertension; Rabbits; Receptors, Drug; Sympathectomy, Chemical; Yohimbine

Derivatives of benzofuran- and indole-2-sulfonamide were prepared for evaluation as topically active ocular hypotensive agents. These compounds were found to be excellent inhibitors of carbonic anhydrase and to lower intraocular pressure in a rabbit model of ocular hypertension. However, the development of these compounds for clinical use was precluded by the observation that they cause dermal sensitization in guinea pigs. A correlation between electrophilicity, as assessed by in vitro reactivity with reduced glutathione, and dermal sensitization potential was further documented.

Topics: Administration, Topical; Animals; Benzofurans; Carbonic Anhydrase Inhibitors; Chemical Phenomena; Chemistry; Chemistry, Physical; Drug Hypersensitivity; Glutathione; Guinea Pigs; In Vitro Techniques; Indoles; Kinetics; Ocular Hypertension; Oxidation-Reduction; Rabbits; Structure-Activity Relationship; Sulfonamides