Orexin B is one of two closely related peptides; the orexins (also known as hypocretins). These small neuropeptides are secreted from orexin-containing neurons, located mainly in the lateral hypothalamus (LH). Orexins function via the binding and activation of two G-protein–coupled receptors (GPCRs); orexin receptor type 1 (OX1) and 2 (OX2).

[Ala(11), D-Leu(15)]orexin-B is a highly potent and selectiveOX2 receptor agonist which can discriminate between the OX1 and OX2 receptors, with a 400-fold selectivity for the OX2 over OX1. [Ala(11), D-Leu(15)]orexin-B is therefore a beneficial tool for addressing the functional roles of OX2.

The L-leucine residue at position 11 of orexin B is important for selectivity to OX2 over OX1. L-Alanine substitution at position 11 and D-leucine substitution at positions 15 maintain the potency of orexin-B to OX2, while significantly reducing the potency for OX1.

Orexins play several vital roles in a range of physiological activities, including: circadian rhythm; feeding behaviour; energy balance; glucose metabolism; neuroendocrine functions; stress-adaptive responses and reward and addiction. Orexins have also been linked to the pathological processes of neurological diseases such as: narcolepsy; depression; ischemic stroke; drug addiction and Alzheimer’s disease.