UCSF scientists have identified novel small molecules which are selective agonists and inverse agonists of the melatonin receptor types MT1 and MT2. The molecules have high in vitro and in vivo potency and potential to be utilized as a novel therapeutic for treating depression, jet lag, and sleep disorders.
Melatonin plays a key role in regulating the circadian clock and sleep/wake cycles. In this invention, the researchers utilized a high-throughput screen to identify novel molecules which can selectively bind to melatonin receptor sub-types and can potently activate (agonists) or reverse the effect of the receptor functions (selective inverse agonists).
The small molecules identified have the following unique properties:
(i) Chemically novel and topologically unrelated to existing melatonin agonists,
(ii) Higher in vitro (nM activities) and in vivo potency (EC50 0.9 mg/kg),
(iii) Initial pharmacokinetics, including demonstrating brain penetration,
(iv) Highly melatonin receptor specific.
There is an unmet need for efficient, selective inhibitors of the melatonin receptors for the treatment of sleep disorders and depression. The existing drugs on the market, such as ramelteon, agomelatin and tasimelteon, are non-selective between the receptor types. At an in vivo probe level, no selective MT1 inverse agonists and few selective MT2 ligands are known. The invention will facilitate the development of highly potent drugs which have the following potential applications:
(i) MT1 inverse agonists for modulating sleep/wake cycles and treating disorders involving misalignment between endogenous rhythms and the environmental light/dark cycle such as in jet lag, delay or advance sleep phase syndrome, depression, among other circadian disorders.
(ii) MT2 agonists for treating pain and anxiety.
(iii) Treatment of neuropathic pain and cancer.
UCSF researchers have used an ultra-large library docking screen to identify chemically novel molecules that can selectively bind to melatonin receptors. The approach involved designing, de novo synthesis, and further structure optimization of the new chemotypes from the docking screen which have favorable docking score and high in vitro and in vivo activity. The result of the screen has identified selective MT1 inverse agonists and selective MT2 agonists that potently affected circadian behavior in a mouse model and have optimal pharmacokinetic properties.
To develop and commercialize the novel therapeutics for the treatment of indications like sleep disorders, depression, anxiety, jet lag, neuropathic pain, and cancer.