Evaluation of the ocular hypotensive response of serotonin 5-HT1A and 5-HT2 receptor ligands in conscious ocular hypertensive cynomolgus monkeys

J Pharmacol Exp Ther. 2003 Jul;306(1):301-9. doi: 10.1124/jpet.103.049528. Epub 2003 Apr 3.

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-(+)-alpha-(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-alpha-methyltryptamine, 5-methoxy-alpha-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.

MeSH terms

  • 8-Hydroxy-2-(di-n-propylamino)tetralin / therapeutic use*
  • Animals
  • CHO Cells
  • Cricetinae
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Female
  • Humans
  • Ligands
  • Macaca fascicularis
  • Male
  • Ocular Hypertension / drug therapy*
  • Receptors, Serotonin / drug effects
  • Receptors, Serotonin / metabolism*
  • Receptors, Serotonin, 5-HT1
  • Serotonin Antagonists / therapeutic use*
  • Serotonin Receptor Agonists / therapeutic use*
  • Transfection

Substances

  • Enzyme Inhibitors
  • Ligands
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT1
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • 8-Hydroxy-2-(di-n-propylamino)tetralin