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

Alarma-Estrany, Pilar; Guzmán-Aránguez, Ana; Huete, Fernando; Peral, Assumpta; Plourde, Robert; Peláez, Teresa; Yerxa, Benjamin R.; Pintor, Jesús

doi:10.1124/jpet.110.178319

Cited by 30 publications

(17 citation statements)

References 21 publications

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“…Low concentrations of this antagonist produced an unexpected potentiation of the action triggered by 5-MCA-NAT. Nevertheless, at higher concentrations (1.5 mM), prazosin had its antagonistic effect blocking melatonin and 5-MCA-NAT actions, indicating that at low micromolar concentrations it acts as a MT 3 receptor antagonist as previously described elsewhere (Dubocovich et al, 2003;Pintor et al, 2003;Alarma-Estrany et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Melatonin Receptors Trigger cAMP Production and Inhibit Chloride Movements in Nonpigmented Ciliary Epithelial Cells

Huete-Toral

Crooke

Martínez-Águila

et al. 2014

J Pharmacol Exp Ther

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Melatonin and its analog 5-MCA-NAT (5-methylcarboxyamino-N-acetyl tryptamine) are active compounds reducing intraocular pressure (IOP). This action is mediated through MT 2 and the putative MT 3 melatonin receptor, producing a transient reduction of IOP that lasts for a few hours and has not yet been characterized. The use of melatonin and its analog are causing a decrease in chloride efflux from rabbit nonpigmented epithelial cells (NPE), possibly explaining the decrease in IOP. Melatonin and 5-MCA-NAT inhibited rabbit NPE chloride release in a concentration-dependent manner, whereas the pD 2 values were between 4.5 6 1.2 and 4.4 6 1.0, respectively. Melatonin hypotensive action was enhanced by the presence of MT 2 antagonists, such as DH97 (N-pentanoyl-2-benzyltryptamine) and 4-P-P-DOT (4-phenyl-2-propionamidotetralin) and by the nonselective melatonin receptor antagonist luzindole. Prazosin (1.5 mM) partially reverses the melatonin action by acting as a selective MT 3 antagonist. However, at 15 nM it acts as an a-adrenergic receptor antagonist, enhancing the melatonin effect. Regarding the intracellular pathways triggered by melatonin receptors, neither phospholipase C/protein kinase C pathway nor the canonical reduction of intracellular cAMP was responsible for melatonin or 5-MCA-NAT actions. On the contrary, the application of these substances produced a concentration-dependent increase of cAMP, with pD 2 values of 4.6 6 0.2 and 4.9 6 0.7 for melatonin and 5-MCA-NAT, respectively. In summary, melatonin reduces the release of chloride concomitantly to cAMP generation. The reduction of Cl 2 secretion accounts for a decrease in the water outflow and therefore a decrease in aqueous humor production. This could be one of the main mechanisms responsible for the reduction of IOP after application of melatonin and 5-MCA-NAT.

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Section: Discussionmentioning

confidence: 99%

Melatonin Receptors Trigger cAMP Production and Inhibit Chloride Movements in Nonpigmented Ciliary Epithelial Cells

Huete-Toral

Crooke

Martínez-Águila

et al. 2014

J Pharmacol Exp Ther

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“…This melatonin, acting in an autocrine way through melatonin receptors present in the ciliary processes (Alarma-Estrany et al, 2009, 2011, could reduce chloride production from the ciliary epithelium as recently described (Huete-Toral et al, 2015).…”

Section: Introductionmentioning

confidence: 92%

TRPV4 activation triggers the release of melatonin from human non-pigmented ciliary epithelial cells

Alkozi

Pintor

2015

Experimental Eye Research

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“…6,8,30 Although the age-related decline of endogenous melatonin levels is uncertain, 31,32 there is generally agreement on the aging effect on the circadian rhythm of melatonin secretion. Duffy et al, 33 investigated the relationship between the timing of plasma melatonin and the sleep-wake cycle in healthy young and old volunteers.…”

Section: Discussionmentioning

confidence: 99%

Effects of Aging on 24-Hour Intraocular Pressure Measurements in Sitting and Supine Body Positions

Mansouri

Weinreb

Liu

2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.To evaluate how aging alters 24-hour measurements of intraocular pressure (IOP) in the sitting and supine body positions. METHODS. Fifteen older volunteers with healthy eyes (ages, 53-71 years) were each housed for 1 day in a sleep laboratory. An 8-hour accustomed sleep period was assigned to each subject. Every 2 hours, measurements of IOP were taken in the sitting and supine positions. Sitting and supine patterns of 24-hour IOP were compared. Simulated 24-hour IOP rhythms in the same body position were determined using cosine fitting of individual 24-hour data. The average postural IOP effects during the diurnal/wake period and the nocturnal/sleep period were compared. Data from this group of older subjects were compared with previously collected data from 16 healthy younger subjects (ages, 18 -25 years) under the same experimental conditions. RESULTS. Within each age group, sitting and supine patterns of 24-hour IOP were similar and parallel. Compared to the younger subjects, the phase timing (simulated peak) of 24-hour IOP was significantly delayed for the older subjects in both body positions. The postural IOP effect for the older subjects was 4.7 Ϯ 0.8 and 4.8 Ϯ 0.8 mm Hg during the diurnal and nocturnal periods, respectively. These postural IOP effects were not significantly different from the postural effects in the younger subjects. CONCLUSIONS. Although aging can significantly delay the phase timing of the 24-hour IOP pattern toward the diurnal/awake period, it may not affect the postural IOP effect during the diurnal and the nocturnal periods. (Invest Ophthalmol Vis Sci. 2012;53:112-116) DOI:10.1167/iovs.11-8763 I ntraocular pressure (IOP) in the human eye is regulated by the rate of aqueous humor formation, the resistance of aqueous humor outflow, and the episcleral venous pressure. IOP varies throughout a 24-hour period due to changes in these physiologic parameters. In healthy younger and nonmyopic subjects, there is 24-hour variation of IOP with a peak value in most individuals occurring in the late nocturnal/sleep period in either sitting or supine body position, independent of posture.1,2 Postural IOP effects, the difference in IOP between the sitting and supine body positions, are not significantly different between the diurnal and nocturnal periods.1 However, an earlier study indicated that the 24-hour IOP variation in the aging population may be different from that in the younger subjects. 3Changes in 24-hour IOP measurements may occur because of age-related structural or functional changes, including alterations in hormonal and neural activities for the regulation of IOP. Circulating levels and timing of glucocorticoids and melatonin as well as the neuronal activities such as the baroreflex may affect the IOP pattern and its variation within a 24-hour period.4 -8 A reported age-related change is the postural IOP effect, 9,10 which is associated with the hydrostatic response in the episcleral venous pressure and the redistribution of body fluid including the choroidal vascular volume...

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

Abstract: 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.

Cited by 30 publications

References 21 publications

Melatonin Receptors Trigger cAMP Production and Inhibit Chloride Movements in Nonpigmented Ciliary Epithelial Cells

Melatonin Receptors Trigger cAMP Production and Inhibit Chloride Movements in Nonpigmented Ciliary Epithelial Cells

TRPV4 activation triggers the release of melatonin from human non-pigmented ciliary epithelial cells

Effects of Aging on 24-Hour Intraocular Pressure Measurements in Sitting and Supine Body Positions

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