advertisement
Abstract #45658 Published in IGR 13-2
Design of novel melatonin analogs for the reduction of intraocular pressure in normotensive rabbits
Alarma-Estrany P; Guzman-Aranguez A; Huete F; Peral A; Plourde Jr R; Pelaez T; Yerxa B; Pintor JJournal of Pharmacology and Experimental Therapeutics 2011; 337: 703-709
Melatonin, the MT(2) melatonin receptor agonist IIK7 [N-butanoyl-2-(2-methoxy-6H-isoindolo[2,1-a]indol-11-yl)ethanamine], and the putative MT(3) melatonin receptor agonist 5-MCA-NAT [5-methoxycarbonylamino-N-acetyltryptamine] have previously been shown to reduce intraocular pressure (IOP) in ocular normotensive rabbits. To gain a better understanding of the structureactivity relationship of compounds that activate MT(2) and MT(3) receptors mediating reductions in IOP, novel melatonin analogs with rationally varied substitutions were synthesized and tested for their effects on IOP in ocular normotensive rabbits (n = 160). All synthesized melatonin analogs reduced IOP. The best-effect lowering IOP was obtained with the analogs INS48848 [methyl-1-methylene-2,3,4,9-tetrahydro-1H- carbazol-6-ylcarbamate], INS48862 [methyl-2-bromo-3-(2-ethanamidoethyl)-1H- indol-5-ylcarbamate], and INS48852 [(E)-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-3- phenylprop-2-enamide]. These compounds produced dose-dependent decreases in IOP that were maximal at 0.1 mM (total dose of 0.259 (mu)g for INS48848, 0.354 (mu)g for INS48862, and 0.320 (mu)g for INS48852) and 1 mM (total dose of 2.59 (mu)g for INS48848, 3.54 (mu)g for INS48862, and 3.20 (mu)g for INS48852), with maximal reductions of 36.0 (plus or minus) 4.0, 24.0 (plus or minus) 1.5, and 30.0 (plus or minus) 1.5% for INS48848, INS48862, and INS48852, respectively. Studies using melatonin receptor antagonists (luzindole, prazosin, and DH97 [N-pentanoyl-2- benzyltryptamine]) indicated that INS48862 and INS48852 activate preferentially a MT(2) melatonin receptor and suggest that INS48848 may act mainly via a MT(3) receptor. The most effective compounds were also well tolerated in a battery of standard ocular surface irritation studies. The implication of these findings to the design of novel drugs to treat ocular hypertension is discussed. Copyright (copyright) 2011 by The American Society for Pharmacology and Experimental Therapeutics.
J. Pintor. Departamento Bioquimica, Escuela Universitaria de Optica, Universidad Complutense Madrid, C/Arcos de Jalon 118, 28037 Madrid, Spain. Email: jpintor@vet.ucm.es
Classification:
11.14 Investigational drugs; pharmacological experiments (Part of: 11 Medical treatment)
5.3 Other (Part of: 5 Experimental glaucoma; animal models)
