Robert Plourde

Effect of 5-mca-nat, a Putative Melatonin Mt3 Receptor Agonist, on Intraocular Pressure in Glaucomatous Monkey Eyes

Purpose5-MCA-NAT, a putative melatonin MT3 receptor agonist, reduced intraocular pressure (IOP) in ocular normotensive rabbit eyes. This study evaluates the effect of topical application of 5-MCA-NAT on IOP in monkey eyes with laser-induced unilateral glaucoma. MethodsA multiple-dose study was performed in 8 glaucomatous monkey eyes. One 25-μL drop of 5-MCA-NAT (2%) was applied topically to the glaucomatous eye at 9:30 am and 3:30 pm for 5 consecutive days. IOP was measured hourly for 6 hours beginning at 9:30 am for one baseline day, one vehicle-treated day, and treatment days 1, 3, and 5 with 5-MCA-NAT. ResultsCompared with vehicle treatment, twice daily administration of 5-MCA-NAT for 5 days reduced (P < 0.05) IOP from 1 hour to 5 hours after the first dose, and the IOP-lowering effects were shown to last at least 18 hours following administration, based on IOP measurements made after the fourth and eighth doses. The ocular hypotensive effect of 5-MCA-NAT was enhanced with repeated dosing. The maximum reduction (P < 0.001) of IOP occurred at 3 hours after each morning dose, and was 4.0 ± 0.5 (mean ± SEM) mm Hg (10%) on day 1, 5.6 ± 0.8 mm Hg (15%) on day 3, and 7.0 ± 1.1 mm Hg (19%) on day 5. Adverse ocular or systemic side effects were not observed during the 5 days of treatment. Conclusions5-MCA-NAT, a putative melatonin MT3 receptor agonist, reduces IOP in glaucomatous monkey eyes. Melatonin agonists with activity on the putative MT3 receptor may have clinical potential for treating elevated IOP.

Lipophilic Modifications to Dinucleoside Polyphosphates and Nucleotides that Confer Antagonist Properties at the Platelet P2Y12 Receptor

Platelet P2Y12 receptors play a central role in the regulation of platelet function and inhibition of this receptor by treatment with drugs such as clopidogrel results in a reduction of atherothrombotic events. We discovered that modification of natural and synthetic dinucleoside polyphosphates and nucleotides with lipophilic substituents on the ribose and base conferred P2Y12 receptor antagonist properties to these molecules producing potent inhibitors of ADP-mediated platelet aggregation. We describe methods for the preparation of these functionalized dinucleoside polyphosphates and nucleotides and report their associated activities. By analysis of these results and by deconstruction of the necessary structural elements through selected syntheses, we prepared a series of highly functionalized nucleotides, resulting in the selection of an adenosine monophosphate derivative (62) for further clinical development.

Design of Novel Melatonin Analogs for the Reduction of Intraocular Pressure in Normotensive Rabbits

Melatonin, the MT2 melatonin receptor agonist IIK7 [N-butanoyl-2-(2-methoxy-6H-isoindolo[2,1-a]indol-11-yl)ethanamine], and the putative MT3 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 MT2 and MT3 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 MT2 melatonin receptor and suggest that INS48848 may act mainly via a MT3 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.