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Abstract #8934 Published in IGR 5-2
Evaluation of the ocular hypotensive response of serotonin 5 HT1A and 5 HT2 receptor ligands in conscious ocular hypertensive cynomolgus monkeys
May JA; McLaughlin MA; Sharif NA; Hellberg MR; Dean TRJournal of Pharmacology and Experimental Therapeutics 2003; 306: 301-309
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 (IOP) lowering efficacy. Thus, their therapeutic utility in the treatment of human glaucoma has been confusing. The authors evaluated the effect of selected 5-HT1A agonists and 5-HT2A receptor antagonists on IOP 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 IOP 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 IOP 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 IOP 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 IOP in the treatment of ocular hypertension and glaucoma in humans.
Dr. J.A. May, Alcon Research, Ltd., 6201 South Freeway, Fort Worth, TX 76134, USA. jesse.may@alconlabs.com
Classification:
11.14 Investigational drugs; pharmacological experiments (Part of: 11 Medical treatment)
