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

The Design of Melatonergic Agonists Part 4 Summary and Prospects by Phil

Summary of features key to dynamics

Over the past twenty years a wealth of knowledge has been acquired concerning the requirements of melatonergic activity. Key structural features and parameters of the ligand have been ascertained for good drug like activity. Also elucidated indirectly is information regarding the complementary receptor.

The acetyl group has a deep lipophilic pocket Face-a is shallow but accommodating The face-b pocket is rather large and its filling enhances affinity Face-b is not continuous with face-a The face-e pocket is spacious The ethylamido aliphatic chain subtends below the indole plane

Figure 33 | Summary of the receptor sub-pockets

The activity of the two currently available melatonergic drugs can be easy rationalised with this working model of the receptor.

Figure 34 | Agomelatine and Ramelteon revisited

Agomelatine is simply the naphthalene bioisostere of indole. This compound is more lipophilic than melatonin and has an appreciably longer half-life. Ramelteon exploits several optimisations: the acetyl group is extended into the lipophilic pocket, the C⁵-O alkyl group is restrained in its active conformation to the face-e pocket, saturation and substitution of the pyrrolic component results in the ethylamido side-chain subtending below the plane. Ramelteon is highly selective and also incredibly potent. Agomelatine on the other hand is far less receptor sub-type selective. In fact, so lax is the selectivity that is also has antagonist activity at the 5-HT_2C receptor - this side-effect is actually very fortuitous. Over stimulation of the 5-HT_2C receptor is the cause of anxiety prevalent during the early phase of treatment with SSRI's. Hence Agomelatine is particularly useful as an SSRI adjunctive agent to offset symptoms of anxiety until receptor desensitisation occurs.

Summary of features tolerated pertaining to kinetic optimisation

It is apparent that the pyrrole group is not involved in H-bonding. Whilst the pyrrole binding pocket is not particularly large, it is tolerant of a wide array of diverse functionality. This provides many opportunities for tailoring the kinetic profile. Indeed all current commercial melatonergic drugs exploit this tolerance to extend the elimination half-life. Homologation of the acetyl group is also a convenient way to enhance lipophilicity and thus drug kinetics.

Future Prospects

With this model the intelligent design of melatonergic agent de novo is quite conceivable. For example, the C² binding pocket is yet to be exploited in commercial agonists. The chiral C³ position is a convenient way of displacing the ethylamido chain, but it is also possible to further promote active conformational attainment. The introduction of an additional cycle may operate synergistically with the C³ chirality.

Figure 35 | Melatonergic drugs of the future?

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