AL-34662 is an indazole derivative drug that is being developed for the treatment of glaucoma. It acts as a selective 5-HT2Areceptoragonist, the same target as that of psychedelic drugs like psilocin, but unlike these drugs, AL-34662 was designed specifically as a peripherally selective drug, which does not cross the blood–brain barrier. This means that AL-34662 can exploit a useful side effect of the hallucinogenic 5-HT2A agonists, namely reduction in intra-ocular pressure and hence relief from the symptoms of glaucoma, but without causing the hallucinogenic effects that make centrally active 5-HT2A agonists unsuitable for clinical use.[1] In animal studies, AL-34662 has been shown to be potent and effective in the treatment of symptoms of glaucoma, with minimal side effects.[2]
Peripherally acting 5-HT2A agonists have been a rich field of research in recent years, with potential glaucoma treatments being the main proposed application for 5-HT2A agonists at present, as centrally acting agonists for this receptor tend to be hallucinogenic and thus their medical usefulness is currently limited to the treatment of psychiatric disorders. While many novel, potent and selective 5-HT2A agonists have been developed for this application,[3][4][5][6][7][8][9][10] retaining peripheral selectivity can be a problem, and several of the more lipophilic compounds closely related to AL-34662 such as those shown below, did cross the blood–brain barrier and produced hallucinogen-appropriate responding in animals.[11]
^Sharif NA, Kelly CR, Crider JY, Davis TL (December 2006). "Serotonin-2 (5-HT2) receptor-mediated signal transduction in human ciliary muscle cells: role in ocular hypotension". Journal of Ocular Pharmacology and Therapeutics. 22 (6): 389–401. doi:10.1089/jop.2006.22.389. PMID17238805.
^Sharif NA, McLaughlin MA, Kelly CR (February 2007). "AL-34662: a potent, selective, and efficacious ocular hypotensive serotonin-2 receptor agonist". Journal of Ocular Pharmacology and Therapeutics. 23 (1): 1–13. doi:10.1089/jop.2006.0093. PMID17341144.
^May JA, Chen HH, Rusinko A, Lynch VM, Sharif NA, McLaughlin MA (September 2003). "A novel and selective 5-HT2 receptor agonist with ocular hypotensive activity: (S)-(+)-1-(2-aminopropyl)-8,9-dihydropyrano[3,2-e]indole". Journal of Medicinal Chemistry. 46 (19): 4188–95. doi:10.1021/jm030205t. PMID12954071.
^US granted 6806285, May JA, Zinke PW, "6-Hydroxyl indole derivatives for treating glaucoma", issued 19 October 2004, assigned to Alcon Inc.
^US granted 6956036, May JA, Feng X, Dantanarayana AP, "6-Hydroxy-indazole derivatives for treating glaucoma", issued 18 October 2005, assigned to Alcon Inc.
^US application 6960608, May JA, Dantanarayana AP, "Fused indazoles and indoles and their use for the treatment of glaucoma", assigned to Alcon Inc.
^US granted 7005443, May JA, Feng Z, "5-Hydroxy indazole derivatives for treating glaucoma", issued 28 February 2006, assigned to Alcon Inc.
^US granted 7208512, Feng Z, Mark R. Hellberg, "Benzodifuranimidazoline and benzofuranimidazoline derivatives and their use for the treatment of glaucoma", assigned to Alcon Inc.
^US granted 7268131, Dantanarayana AP, May JA, "Substituted (1,4)oxazino(2,3-g)indazoles for the treatment of glaucoma"
^US granted 7338972, Dantanarayana AP, May JA, "Substituted 1-alkylamino-1H-indazoles for the treatment of glaucoma", assigned to Alcon Inc.
^May JA, Dantanarayana AP, Zinke PW, McLaughlin MA, Sharif NA (January 2006). "1-((S)-2-aminopropyl)-1H-indazol-6-ol: a potent peripherally acting 5-HT2 receptor agonist with ocular hypotensive activity". Journal of Medicinal Chemistry. 49 (1): 318–28. doi:10.1021/jm050663x. PMID16392816.
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