The current state of melatonin receptor exploration and exploitation: recent and topical advances

The Design of Melatonergic Agonists

by Phil

New perspectives and novel opportunities for the treatment of sleep dysfunction and refractory and major depressive disorders

The page contains a summary presentation of the four part essay series.

Part 1 Introduction
Part 2 The Chemistry of Melatonin
Part 3 Derivative investigation studies
Part 4 Conclusion and Prospects
References

Over the past 30 years the pharmaceutical industry has been witness to an explosion of research into the function of melatonin in man and the use of melatonergic drugs as agents of pharmacotherapeutic and chronobiotic intervention. Through a series of quantitative structure activity relationships our understanding of the melatonergic pharmacophore has been refined. Independent lead optimisation has culminated in the successful trial and release of two novel melatonergic drugs, Ramelteon and Agomelatine. Despite conception as a circadian entraining chronobiotic, the latter has been proven to function beyond expectation and is hailed as the first non-monoaminergic anti-depressant and has far reaching implications for medicine of the 21st century.

Introduction – melatonin
Melatonin is a neurohormone principally associated with the pineal gland. As a modulator of the circadian and seasonal rhythms, an anti-oxidant and antidepressant, melatonin is extensively exploited physiologically - it is also vasoactive, oncostatic, cell-protective and neurotrophic. Abnormal plasma melatonin levels in humans have been linked to many disorders including phase-shifted sleep disorders, dysomnias and depressive and cyclic psychological states. Insomnia is often co-morbid with depression and so the activity of melatonin offers a unique vector for opportunities of chronobiotic and pharmacotherapeutic intervention.
Melatonin Receptors: MT₁, MT₂ & MT₃
In man, the physiological functions of melatonin are mediated by its action at any of the three distinct melatonin receptors: MT₁, MT₂ and MT₃. The latter of these is less well understood but the former are pertinent to the endocrine and central nervous system. These are typical cAMP inhibiting 7-TM G-protein coupled receptors. MT₁ agonism activates protein kinase-B and is responsible for an acute neuronal inhibitory effect. MT₂ agonism induces both soluble guanylate cyclase and protein kinase-C and is likely to be responsible for circadian entrainment.
Light, melatonin and circadian rhythm
	Intrinsically photosensitive retinal ganglion cells transduce environmental photosignals to the suprachiasmatic nuclei via innverations of the retinohypo-thalamic tract The superior cervical ganglia is activated which in turn inhibits the release of melatonin from the pineal gland - hence light acutely suppresses melatonin release Via this pathway daily and seasonal changes are transduced into the organism and are reflected by mean plasma melatonin levels

Pharmacology

Whereas melatonin has unfavourable pharmacokinetics, both Agomelatine and Ramelteon have longer half-lives and are less disposed to cause nocturnal break-through wakefulness. These drugs are more lipophilic than melatonin and extensively distribute into body tissue. Indeed both drugs are more potent and bind with higher affinities than melatonin.

Figure | Comparative pharmacology. EC₅₀ values determined from radio-ligand binding assays

Figure | The elimination kinetics from peak plasma concentrations of common absolute bio-availabilities

Having been proven in the clinical setting, Ramelteon is available as a chronobiotic and hypnotic in the EU. Agomelatine has also been found to possess additional antidepressant qualities. Both are potent MT₁/MT₂ agonists, but Agomelatine is also a selective 5-HT_2C antagonist. This is likely to contribute towards its anti-depressant efficacy and makes it amenable as an adjunctive agent for use with SSRIs, potentially offsetting SSRI induced anxiety.

Table 1 \| Selected Pharmacological Data /nM
	T_½	MT₁IC₅₀	MT₁K_i	MT₂IC₅₀	MT₂K_i	Selectivity	5-HT_2CIC₅₀	5-HT_2CK_i
Agomelatine	2.3h	0.13	0.10±0.01	0.4	0.12±0.02	3.6	270	710
Ramelteon	2.6h	0.21	0.02±0.01	0.05	0.11±0.05	8	-	-
Melatonin	0.7h	0.78	0.08±0.02	0.90	0.38±0.05	1.2	-	-

Elucidation of the Pharmacophore

As reliable X-ray data on human melatonin receptors remains elusive, much of our understanding of the essential pharmacophore has been deduced from the extensive assays of synthetic melatonin derivatives. The goals of such excursions are four-fold: to understand receptor selectivity, to design more potent congeners, to predict agonist or antagonist dynamics & to enhance drug-like pharmacokinetics.

Assaying melatonergic activity

In amphibians melatonin is responsible for night pallor. This enables the convenient assay of melatonergic activity and studies on pigment aggregation of xenopus laevis have been instrumental in developing our understanding.

Sugden et. al., Eur. J. Pharmacol., 1992, 212(3), 405-408

Structure-Activity Relationships

Melatonin as a structural platform offers many opportunities for pharmacophore variation. Catenae and annuli homologation, bio-isosteric substitution, derivatisation and the configuration of absolute conformation are all tailorable facets. For a more detailed analysis of the various modifications, see part 3.


Peripheral substituents	Annular atoms	Di-hedral angles

Amide chain conformational restriction

By restraining the C³ side chain it has been deduced that the anti/gauche conformation, with C^β configured S(-) enables optimal location through the amide binding region.

Methoxy conformation

Assay of the two oxolano- derivatives revealed that in the active conformation the alkoxy substituent is oriented syn relative to the C³ chain. This was achieved through cyclisation of the aliphatic ether via a methylene spacer back onto the tryptamine e-face.

Acetyl homologation
The acetyl binding pocket is deeper than melatonins ethanoyl group would suggest. Homologation enhances binding up to propanoyl but affinity drops steeply thereafter.
Filling the C²-binding site
bromo - full agonist	phenyl - full agonist
carboxymethyl - full agonist	benzyl - antagonist

Indole N1 binding pocket?

Quite diverse bioisosteres of the pyrrole moiety are tolerated. Assay of N-capped, substituted and rearranged derivatives have shown this part of the cyclic system to not be significantly involved in the binding mode. This gives opportunities to tailor the pharmacokinetic profile.

Pyrrole bioisosteres

Furyl	Naphthyl	Chain transfer	Cycloalkyl	N-methyl
* all modifications tolerated, with only mild reductions in activity

From Evidence to Design

We have come up with two new, potential melatonergic agonists, which exploit several of the various optimisations.

From lead to market: Agomelatine and Ramelteon

Takeda Pharmaceuticals and Servier Laboratories arrived at the two effective and novel melatonergic agonists, Ramelteon and Agomelatine. Ramelteon has the methoxy and amide side chains constrained into their active conformations whilst the acetyl group is homologated and both drugs exploit the tolerability of pyrrole bioisosterism to enhance pharmacokinetics. As would be expected by homologation and bioisosteric substitution with lipophilic moieties, both drugs indeed possess superior pharmacokinetic profiles. Optimisation of the pharmacophore has produced very potent drugs.


Ramelteon	Agomelatine

Key Points and Closing Remarks

From our working hypothesis new melatonergic agonists and to a lesser extent antagonists can be predicted.. Several SARs studies support the rational design of melatonin agonists. Ramelteon is a grand example of the success of SARs studies, and its pharmacokinetics and dynamics can be easily rationalised relative to that of melatonin. I do wonder why we need a drug to do what melatonin does rather well; issues of pharmacokinetics can be addressed through delivery or the optimisation of drug formulation. Agomelatine is far more structurally simple than Ramelteon, and it may appear less thought went into its design - one simple bioisosteric substitution. Not a huge difference between it and melatonin, but the substitution of NH for CHCH makes a big impact on patent applications. Indeed Ramelteon may be a victim of its own ingenuity in that designed as a selective agent it lacks the broader serotonergic activity for which Agomelatine is praised and perhaps most famous.

Agomelatine and Ramelteon pharmacodynamics are easily rationalised by interpolation with QSAR studies
These new drugs are selective melatonergic agonists and may be useful for the treatment of a range of mental and sleep disorders
We can expect a rapid clinical embrace of these new agents but also an expansion of the array of melatonergic drugs as new congeners are synthesised

Next: Part 1