PT - JOURNAL ARTICLE AU - Francisco Javier Navarro Gil AU - Fernando Huete-Toral AU - Almudena Crooke AU - Carmen Olalla Dominguez Godinez AU - Gonzalo Carracedo AU - Jesús Pintor TI - Effect of Melatonin and Its Analogs on Tear Secretion AID - 10.1124/jpet.119.259192 DP - 2019 Oct 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 186--190 VI - 371 IP - 1 4099 - http://jpet.aspetjournals.org/content/371/1/186.short 4100 - http://jpet.aspetjournals.org/content/371/1/186.full SO - J Pharmacol Exp Ther2019 Oct 01; 371 AB - Melatonin has been shown to enhance tear secretion associated with dinucleotide diadenosine tetraphosphate. This study investigated the isolated action of melatonin and its analogs, agomelatine, N-butanoyl-2-(2-methoxy-6H-isoindolo[2,1-a]indol-11-yl) ethanamine (IIK7), and 5-methoxycarbonylamino-N-cetyltryptamine (5-MCA-NAT) (10 µl at 100 µM), on tear secretion when applied topically in the rabbit cornea and its relationship with the melatonin MT1, MT2, and MT3/quinone reductase QR2 receptors. The results showed a significant increase in tear secretion, with a maximal effect at 60 minutes for the agonists (138.9% ± 6.5%, 128.9% ± 6.4%, and 120.0% ± 5.2%, respectively; P < 0.05; 100% control) but not for melatonin (101.6% ± 7.9%; P > 0.05). Agonist action was tested combined with the antagonists DH97 (MT2 selective), prazosin (MT3/QR2 inhibitor), and luzindole (nonselective MT membrane receptor) (10 µl at 100 µM). DH97 reversed the effect of agomelatine, IIK7, and 5-MCA-NAT up to 30.85% ± 7.6%,108% ± 7.2%, and 87.01% ± 7.6%, respectively (P < 0.05; 100% control). Luzindole antagonized agomelatine and 5-MCA-NAT up to 67.35% ± 7.6% and 92.12% ± 8%, respectively (P < 0.05). Prazosin only reversed 5-MCA-NAT action up to 84.2% ± 7.7% (P < 0.05). These results suggest different pathways for the agonists to act through MT membrane receptors. Therefore, agomelatine, IIK7, and 5-MCA-NAT act through MT membrane receptors as secretagogues of tear secretion, and these analogs could be considered excellent therapeutic candidates for dry eye treatment.SIGNIFICANCE STATEMENT Currently, dry eye with aqueous deficit is treated by adding artificial tears palliatively. This study shows that topical installation of three melatonin analogs (agomelatine, IIK7, and 5-MCA-NAT), but not melatonin, in therapeutic doses in the rabbit cornea significantly increases tear production, acting through different melatonin membrane receptor subtypes. Therefore, this study suggests that melatoninergic compounds could be considered excellent therapeutic candidates for dry eye treatment and ocular surface diseases occurring with a reduction in tear production.