Abstract
Published investigations of serotonin-1A (5-hydroxytryptamine1A; 5-HT1A) receptor agonists and serotonin-2A (5-hydroxytryptamine2A; 5-HT2A) receptor antagonists in nonprimate species provide conflicting results with regard to their intraocular pressure-lowering efficacy. Thus, their therapeutic utility in the treatment of human glaucoma has been confusing. We evaluated the effect of selected 5-HT1A agonists and 5-HT2A receptor antagonists on intraocular pressure in a nonhuman primate model, the conscious cynomolgus monkey with laser-induced ocular hypertension. Neither selective 5-HT1A agonists [e.g., R-8-hydroxy-2-(di-n-propylamino)tetralin and flesinoxan] nor selective 5-HT2 receptor antagonists [e.g., R-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (M-100907) and 6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxamide (SB-242084)] lowered intraocular pressure in the primate model following topical ocular administration. However, compounds that function as agonists at both the 5-HT1A and 5-HT2 receptors were found to effectively lower intraocular pressure in the model: 5-hydroxy-α-methyltryptamine, 5-methoxy-α-methyltryptamine, 5-hydroxy-N,N-dimethyltryptamine (bufotenine), and 5-methoxy-N,N-dimethyltryptamine. Furthermore, the selective 5-HT2 receptor agonist R-(–)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane lowered intraocular pressure in the primate model, demonstrating a pharmacological response associated with activation of the 5-HT2 receptor. These observations suggest that compounds that function as efficient agonists at 5-HT2 receptors should be considered as potential agents for the control of intraocular pressure in the treatment of ocular hypertension and glaucoma in humans.
Footnotes
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DOI: 10.1124/jpet.103.049528.
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ABBREVIATIONS: IOP, intraocular pressure; 5-HT, 5-hydroxytryptamine (serotonin); 8-OH-DPAT, 8-hydroxy-2-(di-n-propylamino)tetralin; 5-CT, 5-carboxamidotryptamine; SB-206553, 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole; M-100907, R-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol; SB-242084, 6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxamide; DOI, 1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane; R-DOI, R-(–)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane; CHO, Chinese hamster ovary; MAO, monoamine oxidase; DMEM, Dulbecco's modified Eagle's medium; FLIPR, fluorescence imaging plate reader; DMSO, dimethyl sulfoxide; 5-MeODMT, 5-methoxy-N,N-dimethyltryptamine; 5-HOAMT, 5-hydroxy-α-methyltryptamine; 5-MeOAMT, 5-methoxy-α-methyltryptamine; DP-5-CT, N,N-dipropyl-5-carboxamidotryptamine; 5-MeOT, 5-methoxytryptamine; 5-HOMT, 5-hydroxy-N-methyltryptamine; 5-HODMT, 5-hydroxy-N,N-dimethyltryptamine (bufotenine); RS 102221, 8-[5-(2,4-dimethoxy-5-(4-trifluoromethylphe-nylsulfonamido)phenyl-5-oxopentyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride; WB-4101 [2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane hydrochloride.
- Received January 23, 2003.
- Accepted March 31, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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