OX1/2 antagonists

Target: Orexin receptor 1/2, GPCR

Indications: insomnia, addiction

Rationale

The orexin system consists of two neuropeptides known as orexin A and orexin B (or hypocretin-1 and -2) which are derived from a common precursor prepro-peptide by proteolytic processing. The peptides exert their action through binding to two related G-protein coupled receptors termed orexin-1 (OX1R) and orexin-2 (OX2R) receptors.

While the orexin system was initially described as a regulator of feeding behavior (orexin-A stimulates food intake in rodents, hence the name, orexis - greek for appetite), strong genetic evidence indicates a major role for the orexin system in the regulation of the sleep/wake cycle. Human genetic studies have shown that a deficiency in orexin A is responsible for narcolepsy - a sleep disorder characterized by excessive daytime sleepiness, occurrence of sleep attacks during the day and sudden loss of muscle tone triggered by strong emotions. In addition, dogs with genetic mutations in the OX2R gene show a phenotype closely resembling narcolepsy in humans.

Orexin peptides are synthesized by neurons located in the hypothalamus which project to various brain regions with a crucial role in the regulation of wakefulness and sleep.

Orexin neurons in the lateral hypothalamic area (LHA) and posterior hypothalamus (PH) send excitatory projections to regions involved in noradrenergic (locus coeruleus, LC), histaminergic (tuberomammillary nucleus TMN), serotoninergic (Raphe) and cholinergic (laterodorsal/pedunclopontine tegmental nuclei, LDT/PPT) neurotransmission.

Robust support for the use of OX1/2 receptor antagonists in insomnia comes from data obtained in proof of concept human clinical trials.

The orexin receptors are also associated with dopaminergic neurones of the ventral tegmental area (VTA) which are critical elements of the reward system. This dopaminergic pathway is activated by drugs of abuse and a number of studies indicate a critical role for orexin signaling in neuronal pathways leading to addiction and hence to the potential use of OX1R antagonists in the treatment of drug dependence.

OX1/2 receptor antagonists represent an attractive and innovative therapeutic avenue for treating patients suffering from insomnia and other pathological conditions. Our expertise at developing drugs for insomnia and addiction put Evotec in an advantageous position for developing drugs targeting the orexin system.

Status

Evotec has identified novel OX1 and OX2 receptor antagonists and has started hit-to-lead activities in order to optimize their properties.