PT - JOURNAL ARTICLE AU - Jesse A. May AU - Marsha A. McLaughlin AU - Najam A. Sharif AU - Mark R. Hellberg AU - Thomas R. Dean TI - Evaluation of the Ocular Hypotensive Response of Serotonin 5-HT<sub>1A</sub> and 5-HT<sub>2</sub> Receptor Ligands in Conscious Ocular Hypertensive Cynomolgus Monkeys AID - 10.1124/jpet.103.049528 DP - 2003 Jul 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 301--309 VI - 306 IP - 1 4099 - http://jpet.aspetjournals.org/content/306/1/301.short 4100 - http://jpet.aspetjournals.org/content/306/1/301.full SO - J Pharmacol Exp Ther2003 Jul 01; 306 AB - 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. The American Society for Pharmacology and Experimental Therapeutics