iik7 and Ocular-Hypertension

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 structure-activity 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 μg for INS48848, 0.354 μg for INS48862, and 0.320 μg for INS48852) and 1 mM (total dose of 2.59 μg for INS48848, 3.54 μg for INS48862, and 3.20 μg for INS48852), with maximal reductions of 36.0 ± 4.0, 24.0 ± 1.5, and 30.0 ± 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.

Topics: Animals; Dose-Response Relationship, Drug; Drug Design; Eye; Glaucoma; Intraocular Pressure; Isoindoles; Melatonin; Ocular Hypertension; Rabbits; Receptor, Melatonin, MT2; Receptors, Melatonin; Structure-Activity Relationship; Time Factors; Tryptamines

The aim of this study was to investigate the hypotensive effect of the melatonin analogue, N-butanoyl-2-(2-methoxy-6H-isoindolo[2,1-a]indol-11-yl)ethanamine (IIK7), through MT(2)-melatonin receptors and the involvement of the sympathetic nervous system in this action in New Zealand rabbit eyes. The topical application of melatonin or IIK7 produced a reduction in intraocular pressure of 20.2 +/- 5.3% and 38.5 +/- 3.2% respectively. This effect was concentration-dependent; it was blocked by selective MT(2) receptor antagonists and was severely diminished after chemical sympathectomy. Immunohistochemistry and western blot analysis showed the ciliary processes as the site of this action and no co-localization of MT(2)-melatonin receptor with the sympathetic nervous system was observed. The beta-adrenergic agonists, terbutaline and salbutamol, potentiated the hypotensive effect of IIK7 reducing intraocular pressure (IOP) 41.75 +/- 4.26% and 44.7 +/- 5.6% respectively. Also, IIK7 in presence of the nonspecific protein phosphatase inhibitor okadaic acid, lowered IOP 32.2 +/- 4.5% and in presence of forskolin plus 3-isobutyl-1-methylxanthine decreased IOP in 32.2 +/- 5.47%. These data suggest that the melatonin agonist IIK7 reduces intraocular pressure by acting through MT(2)-melatonin receptors presumably decreasing aqueous humour formation. Also, in the presence of beta-adrenoceptor agonists MT(2)-melatonin receptors activity increase their ability to reduce IOP.

Topics: 1-Methyl-3-isobutylxanthine; Administration, Topical; Adrenergic beta-Agonists; Albuterol; Animals; Aqueous Humor; Colforsin; Dose-Response Relationship, Drug; Intraocular Pressure; Isoindoles; Melatonin; Ocular Hypertension; Okadaic Acid; Rabbits; Receptor, Melatonin, MT2; Sympathectomy, Chemical; Sympathetic Nervous System; Terbutaline