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VOL. 73 (4), 947-962, 2007 MELATONIN MAKES ME FEEL AWAKE!...

provided by INSPIRE. Therefore, dose-response analysis and

anatagonism experiments were performed with the best three

synthetic compounds. Dose-response analysis was OK, as expected,

but surprisingly antagonism analysis demonstrated that at least two

of the three tested compounds were acting through MT2 receptors
rather than on MT3 as expected. Another couple of questions arise:
Do we have more than the MT3 melatonin receptor controlling IOP?
Is there a MT2 as well?

MT2 receptors and IOP

It was quite evident by our previous results that a MT2 melatonin
receptor may exist and that this receptor would control IOP together
with the MT3 melatonin receptor. So, acting in a similar way as we
proceeded with 5-MCA-NAT we looked for a selective MT2 agonist,
N-butanoyl-2-(2-methoxy-6H-isoindolo [2,1-a]indol-11-yl) ethanami-
ne, abbreviated IIK7. The application of this compound to the
experimental animals reduced IOP, and this reduction was avoided
by the MT2 antagonists 4-PPDOT and DH-97.

The discovery of a receptor for melatonin that belongs to the MT2
subtype permitted us to expand our knowledge on the melatonin
physiology in the eye since this receptor has been cloned and there
are antibodies raised against it. In this sense out studies using MT2
receptor antibodies permitted to localise this receptor in the ciliary
processes, which is the place where the aqueous humour is
synthesised (Figure 4). So combining the fact that melatonin and
IIK7 reduce IOP and that the receptors are located in the ciliary
body it seems clear that MT2 receptors should reduce the production
of the aqueous humour and that reduction may be the reason for a
decrease in IOP. This makes sense since MT2 receptors are negatively
coupled to adenylate cyclase. Beta-adrenergic receptors are typically
antagonised in the pharmaceutical treatments for glaucoma, and
they are positively coupled to adenylate cyclase. Altogether the
topical application of IIK7 or melatonin finally inhibits PKA with
the concomitant fall in the IOP, which at the end is the same ultimate
effect beta-receptor antagonists produce.

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